PI3Ks activate critical signaling cascades and have multifaceted regulatory functions in the immune system. Loss-of-function and gain-of-function mutations in the PI3Kδ isoform have revealed that this enzyme can substantially impact immune responses to infectious agents and their products. Moreover, reports garnered from decades of infectious disease studies indicate that pharmacologic inhibition of the PI3K pathway could potentially be effective in limiting the growth of certain microbes via modulation of the immune system. In this review, we briefly highlight the development and applications of PI3K inhibitors and summarize data supporting the concept that PI3Kδ inhibitors initially developed for oncology have immune regulatory potential that could be exploited to improve the control of some infectious diseases. This repurposing of existing kinase inhibitors could lay the foundation for alternative infectious disease therapy using available therapeutic agents.

The phosphoinositide 3-kinases (PI3Ks) are lipid kinases that serve a variety of important functions such as cell survival, metabolism, proliferation, and migration (1, 2). The first PI3K inhibitors (PI3Ki) to be discovered were wortmannin (3) and LY294002 (4), which became notable in the late 1990s as tools for defining the functions of these enzymes in cell biology. With the advent of the twenty-first century, more potent and specific inhibitory agents have been optimized and designed to target one or more of the class I PI3K isoforms (5). This has resulted in several U.S. Food and Drug Administration–approved PI3Ki drugs such as idelalisib (6, 7), duvelisib (8), copanlisib (9), and alpelisib (10). Because the PI3K pathway has long been known to be dysregulated in cancer, the initial applications of PI3Ki have been in the oncology field. However, class I PI3Ks are also activated via a number of receptor classes in immune cells and have essential functional roles in immune responses; thus, the potential use of PI3Ki in autoimmune and inflammatory diseases have also been explored (11).

Upon activation, class 1 PI3Ks catalyze specific lipid phosphorylation reactions to generate key second messengers within the inner leaflet of the plasma membrane (12). Specifically, PI3Ks catalyze the addition of a D3 phosphate to certain phosphoinositide (PI) species to generate phosphatidylinositol-(3,4,5)-trisphosphate (13), or the related PI3K product phosphatidylinositol-(3,4)-bisphosphate (14, 15). Although the four class I PI3K isoforms PI3Kα, β, δ, and γ all generate these two second messengers, they differ in their regulation and coupling to receptors (16). Moreover, they have distinct expression patterns, with PI3Kα and PI3Kβ being ubiquitous, whereas PI3Kδ and PI3Kγ are largely restricted to hematopoietic cells (Table I). Phosphatidylinositol-(3,4,5)-trisphosphate and phosphatidylinositol-(3,4)-bisphosphate bind to and activate other signaling proteins, which are also drug targets, such as the tyrosine kinase Btk (17, 18), the serine-threonine kinase Akt (19), and the mammalian target of rapamycin (mTOR), a serine-threonine kinase which functionally interacts with Akt (20, 21). Numerous additional PI-binding proteins are involved in mediating cellular responses upon PI3K activation, including adaptor proteins, cytoskeletal regulators, and regulators of monomeric GTPases (22, 23). A large body of evidence accumulated over decades has highlighted the essential role PI3K-dependent signaling pathways in immune cell differentiation and proliferation (24), metabolism (25), migration (26, 27), and effector functions (11, 28). The balanced activity of this pathway is maintained by PI phosphatases, such as SHIP and PTEN, that are critical to prevent dysregulation and aberrations of the immune system (29, 30).

Table I.
PI3K isoform expression, mutations, and small molecule inhibitors
PI3K Isoform (Gene Name)Cell Types ExpressingMutations (GOF/LOF)Approveda (with Indications) or Investigationalb Agents
α (PIK3CAUbiquitous GOF mutations frequent in solid tumors, tissue overgrowth syndromes; hotspots: H1047R, E542K, E545K Alpelisiba (ER/PR+ breast cancer with PIK3CA mutation, combination with fulvestrant); taselisibb, TAK-117b, AZD8835b,c 
β (PIK3CBUbiquitous Rare GOF (E1051K) AZD8186b, GSK2636771b 
γ (PIK3CGHematopoietic Rare LOF mutations (R1021P and frameshift) IPI-549b 
δ (PIK3CDHematopoietic, some expression in endothelium and stroma GOF mutations (E1021K and others) in APDS; rare LOF mutations Idelalisiba (relapsed CLL with rituximab, relapsed FL and SLL); duvelisiba,d (R/R CLL/SLL and R/R FL); copanlisiba,c (relapsed FL) 
PI3K Isoform (Gene Name)Cell Types ExpressingMutations (GOF/LOF)Approveda (with Indications) or Investigationalb Agents
α (PIK3CAUbiquitous GOF mutations frequent in solid tumors, tissue overgrowth syndromes; hotspots: H1047R, E542K, E545K Alpelisiba (ER/PR+ breast cancer with PIK3CA mutation, combination with fulvestrant); taselisibb, TAK-117b, AZD8835b,c 
β (PIK3CBUbiquitous Rare GOF (E1051K) AZD8186b, GSK2636771b 
γ (PIK3CGHematopoietic Rare LOF mutations (R1021P and frameshift) IPI-549b 
δ (PIK3CDHematopoietic, some expression in endothelium and stroma GOF mutations (E1021K and others) in APDS; rare LOF mutations Idelalisiba (relapsed CLL with rituximab, relapsed FL and SLL); duvelisiba,d (R/R CLL/SLL and R/R FL); copanlisiba,c (relapsed FL) 
a

Approved agents.

b

Investigational agents.

c

Dual PI3Kalpha/δ inhibitors.

d

Dual PI3Kdelta/γ inhibitor.

Abbreviations used in this table: ER/PR, estrogen receptor/progesterone receptor; FL, follicular lymphoma; R/R, relapsed or refractory; SLL, small lymphocytic lymphoma.

The PI3K signaling pathway can become dysregulated and result in aberrant downstream effector functions and excessive cell growth and proliferation, which is characteristic of many cell malignancies (31). The role of PI3K dysregulation in development of solid tumors is well established; for example, the activation of PI3Kα (32) and the loss of the regulatory phosphatase PTEN (33) have been linked to pathogenesis of colorectal cancers in humans, and activating mutations in PI3Kα are present in subtypes of breast cancer (34) and other malignancies (Table I). Aberrant activation of PI3Kδ and PI3Kγ have been associated with multiple blood cancers, particularly B cell malignancies (35). Thus, it comes as no surprise that PI3Ki have been employed as targeted therapy in oncology, either as a sole agent or in combination with other therapeutic agents (36, 37). The first U.S. Food and Drug Administration–approved PI3Ki was the PI3Kδ inhibitor (PI3Kδi) idelalisib, which is used in combination with rituximab for the treatment of refractory or relapsing chronic lymphocytic leukemia (CLL) (38) (Table I). More recently alpelisib, which targets PI3Kα, has been approved for managing certain types of breast cancers (10). Other new generation PI3Ki, such as the dual PI3Kδ/PI3Kγ inhibitor duvelisib (39) and PI3Kδ/PI3Kα dual inhibitor copanlisib (40), have been approved for use in relapsing CLL and follicular lymphoma, respectively. Many more PI3Ki are in different phases of clinical trials for oncology indications (36).

PI3Ki also show significant promise for use in treating a number of inflammatory (41) and autoimmune disease conditions (42, 43). Although immune-mediated inflammatory diseases have different etiologies and complex pathogenesis, common underlying processes can include loss of tolerance to self-antigens, aberrant activation of a wide array of immune cells, and increased cell migration into inflamed tissues. Substantial evidence suggests that elevated PI3K pathway activation can lead to loss of tolerance, aberrant immune activation, and autoantibody production (4446). Evidence from mouse models highlights the therapeutic potential of PI3Ki in attenuating inflammation in asthma (47, 48), chronic obstructive pulmonary disorder (49, 50), rheumatoid arthritis (51), and systemic lupus erythematous (52, 53). In these disease models, amelioration of immune cell hyperactivation phenotypes and reduced migration of inflammatory cells into inflamed tissues has been observed upon PI3Ki treatment. Clinical trials in humans also indicate that the PI3Kδi GSK2269557 (nemiralisib) could potentially be of benefit in management of chronic obstructive pulmonary disorder (54), although a recent phase 2b trial did not meet its clinical efficacy endpoints. Together, these studies indicate that PI3Ki can suppress some deleterious immune effector responses in the context of chronic diseases.

The PI3Kδ isoform is distinguished by its selective expression in immune cells (Table I) and its well-demonstrated importance in immune function. Investigations in genetically modified mice and human patients carrying natural mutations in PI3Kδ have provided important insights into the spectrum of immune functions controlled by this enzyme. Early studies generating loss-of-function (LOF) mutations in mice demonstrated critical roles for PI3Kδ in activation of immune cells (24, 55, 56). Despite a clear humoral immune deficiency, mice with PI3Kδ LOF develop autoimmune intestinal inflammation, which was attributed to defects in regulatory T cell (Treg) function (24, 57). Humans with very rare PI3Kδ LOF mutations have been reported (Table I) and suffer from immunodeficiency as well as autoimmune manifestations that include inflammatory colitis (58, 59). Together, these studies indicate dual roles of PI3Kδ in immune regulatory as well as effector function, as further elaborated below. Mice with LOF mutations in PI3Kγ, the other PI3K isoform selectively expressed in hematopoietic cells, develop mild defects in lymphocyte function and substantial defects in myeloid cell function (6062). Remarkably, dual PI3Kδ/γ deficiency results in an autoinflammatory disease associated with T cell lymphopenia and defective Treg function (63). Human LOF mutations in PI3Kγ have also been reported (Table I) and in one case were associated with Ab defects and autoimmune complications, including T cell infiltration into gut and other tissues (64). Thus, whereas PI3Kδ and PI3Kγ have distinct functions in immune cells, they both appear to play roles in balancing regulatory and inflammatory pathways.

Since 2013, it has become apparent that gain-of-function (GOF) mutations in human PI3Kδ account for a significant number of cases of common variable immunodeficiency of previously unknown cause. Patients bearing PI3Kδ GOF mutations, the most common of which give rise to an E1021K amino acid substitution, exhibit a condition now referred to as activated PI3Kδ syndrome (APDS) (6568) (Table I). APDS in humans (69, 70) and modeled in mice (7174) is marked by exaggerated T and B cell activation and eventual immunosuppression. Patients frequently exhibit autoimmune manifestations that are also observed in mouse models (75, 76). These somewhat contradictory phenotypes associated with the mutation of this protein suggests the requirement for fine tuning of PI3K activity to balance immune effector and regulatory cell functions.

An important finding in patients with activating mutations in PI3Kδ is their predisposition to a wide variety of infectious agents (77, 78). APDS patients suffer from recurrent respiratory tract infections as well chronic viral infections. Common agents causing respiratory infection include bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae, and viruses, such as respiratory syncytial virus or parainfluenza virus (67, 79). Systemic viral infection caused by CMV, EBV, and HSV are also observed (67, 80). Finally, APDS patients are also prone to gastrointestinal bacterial diseases, such as Clostridium difficile infection (78), and parasitic infections, such as toxoplasmosis (81).

PI3Kδi, such as leniolisib (82), as well as the inhalant inhibitor nemiralisib (54, 74) are currently been investigated as potential therapies in ameliorating the symptoms of APDS and are showing great promise for the future. Indeed, in a small clinical study, leniolisib reversed many clinical features of APDS (82). Thus, in addition to hematologic malignancies and immune-mediated inflammatory diseases, APDS is a third type of clinical indication in which treatment with PI3Ki may provide benefits, indicating the wide therapeutic potential of this class of drugs. The application of potentially immune-suppressive drugs to treat an immunodeficiency characterized by recurrent infections may seem paradoxical and highlights the complex roles of PI3Kδ in both immune regulation and effector function. Interestingly, evidence is accumulating to suggest additional potential opportunities for PI3Kδi in managing diseases of infectious origin when carefully applied. Below, we summarize evidence that PI3Ki can improve early immune responses to some infectious agents by boosting innate immunity and inhibiting regulatory responses.

Infectious agents continue to be a major cause of morbidity and mortality globally (83) and can sporadically give rise to major global outbreaks as illustrated in particularly dramatic fashion by SARS-CoV-2. A number of experimental models have investigated the function of PI3Ks in responses to infectious diseases, yielding interesting and, in some cases, quite surprising results. Genetic evidence as well as results of PI3Ki treatment studies collectively suggest that PI3K inhibition can have immune stimulatory potential while concurrently hampering immune-suppressive responses, and this shift can substantially improve the early course and progression of the disease. As described below, PI3Ki can have impact at several levels, including pathogen replication within host cells, the early innate immune response, regulatory cell function, and effector mechanisms of adaptive immunity.

Impact on pathogen replication in host cells.

There are early findings suggesting that PI3Ki can control pathogen replication within infected target cells. For example, pan-PI3K and Akt inhibitors were shown to markedly reduce HIV viral production in infected macrophages in vitro (84, 85). Similarly, the PI3K pathway appears to play roles in promoting replication of Marek disease virus (86) as well as the MERS coronavirus (87). Pan-PI3Ki also show antimicrobial effects in infections caused by nonviral pathogens such as Toxoplasma gondii (88) or Cryptosporidium parvum (89). In a study showing that mycobacterial infection activates the PI3K pathway, hyperactivation of PI3K signaling via PTEN deletion was found to increase susceptibility of various cell types to mycobacterial infections that was reversible by PI3Ki treatment (90). In some cases, specific PI3K-dependent mechanisms promoting pathogen replication have been defined, such as PI3K-dependent activation of cdc42, promoting pathogen entry, (89) or PI3K-dependent suppression of Nox4 expression (88). However, the challenge in interpreting these studies is that they are in vitro and use early generation PI3Ki drugs with potential for off-target effects.

Enhanced stimulation of innate responses from myeloid cells.

A prompt and effective innate immune response early in the course of an infection is critical for controlling the acute phase of a disease (91) as well as shaping the magnitude of adaptive immunity (92). Although the inhibition of PI3Kδ impairs Ag receptor signaling in B and T cells (24), multiple lines of evidence suggest that it can enhance innate immune signaling via pattern recognition receptors in myeloid cells such as macrophages and dendritic cells (9395). Although the mechanisms for this enhancement are not entirely clear, inhibiting PI3Kδ in myeloid cells is known to reduce activation of the PI-binding kinase Akt (96, 97), which has been implicated in dampening TLR signaling (98). Akt1-deficient macrophages were found to have altered expression of microRNAs, including reduction in let-7e, which can repress TLR expression and signaling (99). Akt also phosphorylates and inactivates the transcription factor FOXO1, which has been reported to be a positive regulator of TLR expression and signaling in macrophages (93); thus, inhibition of PI3K and its downstream target Akt can enhance expression of direct targets of FOXO1, which include proinflammatory molecules such as TLR4, iNOS, and TNF-α (93). Conversely, inhibition of either PI3K or Akt are also reported to reduce generation of an anti-inflammatory IL-10–producing macrophage phenotype (98).

Enhanced TLR signaling in the presence of PI3Ki can lead to increased proinflammatory cytokine responses to LPS and other TLR ligands such as CpG, TLR5/flagellin, or TLR2/synthetic bacterial lipoprotein (94, 100, 101). PI3K-deficient dendritic cells exhibited elevated p38 MAP kinase activation and secreted larger quantities of proinflammatory cytokine IL-12p40 in response to multiple TLR agonists (102). We have reported that PI3Kδ-deficient B cells also show elevated production of IL-12 but reduced IL-10 upon stimulation with LPS or CpG (103). PI3Ki treatment has been found to functionally improve antitumor responses induced by dendritic cell–based vaccines and TLR agonists in mouse models (104). As discussed further below, impact of PI3Ki on antitumor responses also likely involves effects at the level of Tregs and T effector and memory cell programming. PI3Kδ-deficient macrophages also exhibit elevated p38 activation and increased production of IL-12 and NO (97); however, their bactericidal effects against extracellular bacteria, such as Escherichia coli and Salmonella typhimurium, are compromised (97). This enhanced inflammatory macrophage response following PI3Kδ inhibition may well be protective in the control of intracellular pathogens, such as Leishmania major or Listeria monocytogenes (discussed further below), in which NO production is critical for protective innate immunity (105).

Similar enhancement in macrophage cell activation has been observed in in PI3Kγ-deficient macrophages from humans and mice, including prolonged TLR-induced NF-κB activation and increased production of IL-12 and NO synthase 2 (60, 64), suggesting that other PI3K isoforms may play analogous regulatory roles. This ability of PI3Kγ inhibition to promote macrophage differentiation toward a proinflammatory phenotype is the basis for ongoing clinical trials assessing PI3Kγ inhibitor for treatment of solid tumors (106). Conversely, enhanced PI3K pathway activity caused by PTEN deficiency led to reduced expression of proinflammatory cytokines, such as TNF-α (107), and, consequently, an inability to clear intracellular L. major (108). PI3Kδ inhibition was reported to enhance type 1 IFN responses in bronchial epithelial cells induced by the TLR3 ligand Poly(I:C) while concurrently reducing expression of the regulatory molecule PD-L1 (109). Thus, in addition to enhancing innate responses of macrophages and dendritic cells, PI3Kδ may also potentially enhance innate antiviral responses in nonimmune cell types.

Impairment of regulatory immune cell function.

Concomitant with enhanced innate immune responses, there is also evidence that PI3Kδ inhibition can suppress regulatory lymphocyte functions. PI3Kδ is required for both expansion and maintenance of the Foxp3+ Treg population and for function of Tregs in preventing colitis in mouse models (57). Human Tregs are highly sensitive to PI3Kδi treatment, which inhibited their proliferation and suppressive function (110), potentially contributing to autoimmune manifestations developing in PI3Kδi-treated leukemia patients. Interestingly, a human subject with genetic deficiency in PI3Kγ exhibited reduced Treg frequencies and developed colitis, and PI3Kγ-deficient mice also develop defects in Treg numbers and T cell infiltration into the colon when exposed to the more diverse microbiota of pet store mice (64). Impairment of Treg function has been proposed as the underlying mechanism explaining why PI3Kδ inhibition can paradoxically enhance antitumor responses (111113).

One of the key functions of Tregs is the release of the suppressive cytokine IL-10 to modulate immune responses to infectious diseases, limiting responses from effector T cells, myeloid cells, and other innate cells (114). Insights from L. major infection studies indicate that mice genetically deficient in PI3Kδ are more resistant to infection, and this is marked by rapid parasite clearance and significantly reduced lesion sizes (115). Resistance was associated with markedly reduced Treg expansion and homing to diseased tissue (115). Resistance to L. major infection was also observed in mice rendered PI3K-deficient by mutation of the p85α regulatory subunit (102). Prophylactic or therapeutic treatment with PI3Kδi idelalisib also markedly improved resistance to both L. major and Leishmania donovani parasites and this resistance was associated with reduced Treg numbers (116). The authors concluded that reduction in Treg function allowed for effective immunity to L. major despite observed reductions in effector T cell responses as indicated by IFN-γ production and proliferation (115). This would suggest that in the context of this infection, the reduction in the magnitude of the suppressive functions of Tregs may be important for unleashing beneficial host responses.

Bacterial infection models have also supported the idea that PI3Kδ inhibition can lead to improved early immunity. Studies with L. monocytogenes infection found that PI3Kδ deficiency in mice resulted in significantly improved bacterial clearance from the spleen and liver (117). Improved control was observed within the first few days postinfection (117), which is prior to the development of Listeria-specific CD8 T cells essential for complete bacterial clearance (118). Studies with S. pneumoniae respiratory infection found that genetic PI3Kδ deficiency or treatment with PI3Kδi improved survival (74). In this model, PI3Kδ inhibition reduced early mortality (within 4 d of infection), which occurs via Ab-independent innate immune mechanisms. This suggests that, as also seen in Leishmania infection, PI3Kδ inhibition can enhance protective innate immune responses to bacteria and could be useful in limiting pathogen burden.

In addition to the impact on Tregs, there is evidence that PI3Kδ is critical for development and function of regulatory B cells. PI3Kδ is known to be required for development of certain B cell subsets, such as the peritoneal B1 cells and marginal zone B cells (119), which are also known as innate B cells and have the capacity to make the suppressive cytokine IL-10 (120). Conversely both B1 cells and transitional B cells, which are also known for secreting IL-10 and exerting regulatory functions (120122), are increased in mice and humans with PI3Kδ GOF mutations (71, 72, 74, 123). In addition to the role of PI3Kδ in development of IL-10–producing B cell populations, findings in our laboratory suggest that IL-10 secretion by B1 cells is reduced by acute pharmacologic inhibition of PI3Kδ (F. Adefemi, C. Onyilagha, N. Jayachandran, S. Hou, P. Jia, J. Uzonna, and A. Marshall, unpublished observations). We have recently observed an improved control of Trypanosoma congolense in the acute phase (first week) of infection in PI3Kδ-inhibited mice, which is associated with reduced IL-10–producing B cells and increased NO production by myeloid cells in the peritoneal cavity (F. Adefemi, C. Onyilagha, N. Jayachandran, S. Hou, P. Jia, J. Uzonna, and A. Marshall, manuscript in preparation). Our results indicate that B cells are the main IL-10–producing cell type in early T. congolense infection, concurring with previous studies (124), and suggest that impairment of regulatory B cell function via PI3Kδ inhibition improves early innate control of parasite growth, similar to observations in Leishmania and bacterial infections.

Studies in the S. pneumoniae infection model additionally indicate that PI3Kδ activity is critical for generation of an IL-10–producing regulatory B cell (Breg) population that inhibits early innate responses controlling this infection (74). Stark and colleagues (74) observed that introduction of germline or B cell–specific p110δ GOF mutation in mice led to marked increases in B1 cells as well as a CD19+B220 IL-10–producing B cell population that were located in the spleen, bone marrow, and lungs. These latter cells, although rare in wild-type mice, were completely absent in PI3Kδ LOF mutant mice, indicating a strong link between the development of this IL-10–producing B cell population and PI3Kδ activity. Interestingly, the increased susceptibility to S. pneumoniae respiratory infection observed in the GOF mutants was mediated by these IL-10–producing Bregs in the lungs, and treatment with the inhalant PI3Kδi nemiralisib dramatically reduced IL-10 secretion by PI3Kδ GOF B cells, potentially contributing to its therapeutic effect in the context of S. pneumoniae infection (74).

Together, these reports support the model that PI3Kδ inhibition can lead to a less suppressive immune milieu, including both reduced Treg and Breg function, that unleashes the enhanced innate responses during early acute phases of infection (Fig. 1A).

FIGURE 1.

Schematic model illustrating the impact of acute or chronic PI3K inhibition during the immune response to infectious disease. (A) Illustration of the opposite effects of acute PI3K inhibition on innate immune responses and regulatory lymphocytes that can lead to improved early pathogen control. Although signals leading to early T cell activation and proliferation can be compromised by PI3Ki treatment, this can be counterbalanced by enhanced innate immune activation and reduced regulatory responses, unleashing early effector responses. (B) The potential impact of long-term PI3K treatment on adaptive immune responses is depicted. Ab responses can be impaired because of direct effects of PI3Ki on GC B cells and TFH. The quantity and quality of T cell memory can also be impacted; however, its currently unclear whether this is advantageous or detrimental in different infectious disease contexts.

FIGURE 1.

Schematic model illustrating the impact of acute or chronic PI3K inhibition during the immune response to infectious disease. (A) Illustration of the opposite effects of acute PI3K inhibition on innate immune responses and regulatory lymphocytes that can lead to improved early pathogen control. Although signals leading to early T cell activation and proliferation can be compromised by PI3Ki treatment, this can be counterbalanced by enhanced innate immune activation and reduced regulatory responses, unleashing early effector responses. (B) The potential impact of long-term PI3K treatment on adaptive immune responses is depicted. Ab responses can be impaired because of direct effects of PI3Ki on GC B cells and TFH. The quantity and quality of T cell memory can also be impacted; however, its currently unclear whether this is advantageous or detrimental in different infectious disease contexts.

Close modal

The downside of PI3Ki treatment: impact on lymphocyte effector responses.

One potential drawback of PI3Ki treatment is the negative impact that it can have on long-term lymphocyte effector responses (Fig. 1B). PI3Kδ is reported to have roles in generating CD4 and CD8 T cell effector responses, such as the production of IFN-γ–producing Th1 cells (115, 125, 126) and CD8 effector cell expansion (117, 127). In L. major infection, the PI3Kδ LOF mutation altered the clonal expansion of CD4 T cells (115), affecting their recruitment to inflamed sites and their secretion of effector cytokines (IFN-γ and TNF). In the same vein, the magnitude of primary and secondary CD8 responses were compromised because of cell-intrinsic defects in PI3Kδ LOF CD8+ cells (117). Thus, in both parasite and bacterial infection models, improved early control of the pathogen occurs despite reduced expansion of effector T cells. Similarly, CD8 T cell expansion is reduced in influenza infection, resulting in reduced viral clearance at day 10 postinfection in PI3Kδ LOF mice (128); data on viral load at early time points were not reported in this study. Hence, another potential caveat of PI3Kδ inhibition is the significant alterations to effector T cell responses. However, these studies have relied on mouse models with congenital genetic deficiency in PI3Kδ, and it remains to be determined whether partial pharmaceutical inhibition of PI3K activity during the acute phase of infection has a major impact on generation of T cell effector responses.

PI3Kδ is also critical for the development of follicular helper T cells (TFH) and germinal centers (GC) (55, 119, 129), which are required for generation of high-affinity Ab responses and memory B cells. Mice with PI3Kδ LOF mutation fail to develop GC, have severely reduced Ab titers, and fail to develop Ag-specific Abs to model immunogens such as TNP-KLH (24). This downside to PI3Kδ inhibition on GC is observed in the T. congolense infection model, in which we observed that PI3Kδ LOF mutant mice show severely impaired development of GC B cells and TFH cells, as well as impaired generation of Trypanosome-specific Abs, emphasizing a highly deficient T cell–dependent Ab response (Adefemi et al., in preparation). Thus, although early innate control of T. congolense is improved in mice genetically deficient in PI3Kδ activity, they fail to generate Ag-specific Abs required to control subsequent waves of parasitemia, resulting in early mortality. However, we find that treatment of wild-type mice with PI3Kδi maintains the improved early parasite control and shows milder impact on GCs and allows production of Ag-specific Abs sufficient to clear the first wave of infection (Adefemi et al., in preparation). This illustrates the distinct functional impact of congenital genetic deficiency versus acute pharmacologic inhibition and suggests that use of PI3Kδi could potentially be selectively applied during the acute phase of the disease to improve early innate control of infection without severely compromising adaptive immunity.

Another potential challenge with PI3Kδi treatment is the possibility of compromised adaptive immunity recall responses due to impact on memory cell differentiation. Secondary anti-Leishmania responses were found to be severely impaired in PI3Kδ-deficient mice (130), as characterized by reduced delayed-type hypersensitivity responses and less efficient parasite control. The latter is in stark contrast to the improved control of parasitemia in the primary response to L. major. Similarly, the CD8 T cell memory responses to influenza virus and Listeria infection are also impaired, although not entirely absent, in mice with genetic PI3Kδ deficiency (117, 128). Despite these results in genetic models, recent studies have reported that ex vivo treatment of CD8 T cells with PI3Kδi can delay CD8 effector differentiation, maintaining a less differentiated memory-like phenotype associated with more potent antitumor immune responses in a number of cancer models (131, 132). In one of the studies, it was observed that idelalisib-treated CD8 T cells were able to persist longer in vivo and had improved capacity to infiltrate and regress tumors (131). Thus, at least in the context of antitumor immunity, transient inhibition of PI3Kδ in CD8 T cells does not compromise their memory and effector functions. Regarding humoral immune memory, genetic deficiency of PI3Kδ leads to significantly compromised primary and recall Ab responses to thymus-dependent Ags (56); however, the impact of acute pharmaceutical PI3Kδ inhibition on generation of TFH or B cell memory in the context of infection has not been reported to our knowledge.

Hence, whereas insights from a variety of disease models collectively support further exploration of the potential of PI3Kδi in infectious disease therapy, we should be cognizant of the potential effects on long-term lymphocyte effector functions that may develop with chronic treatment.

Based on available data discussed above, we propose the following model describing the overall immune regulatory impact of PI3Ki treatment on host responses to infection (Fig. 1A). In the early acute phase of infection, PI3Ki have opposing effects on innate myeloid cell responses, which are enhanced, and regulatory T and B lymphocyte responses, which are impaired. Enhancement of early disease resistance is therefore due to the combined impact of PI3Ki on the following: 1) myeloid cell–intrinsic activation of proinflammatory pathways (TLR, NF-κB, type I IFN, etc.) and 2) the regulatory lymphocyte-intrinsic generation of anti-inflammatory mediators such as IL-10. The resulting enhanced and deregulated innate responses can lead to improved early control of pathogen replication and spread. For some intracellular pathogens, PI3Ki can have additional direct effects on replication within target cells. PI3Ki can concurrently reduce the intrinsic ability of T and B lymphocytes to generate adaptive immune responses due to impaired Ag receptor and cytokine receptor signaling and reduced clonal expansion; however, this may be partially compensated by enhanced innate responses and impaired Treg/Breg function, allowing a significant level of lymphocyte priming and effector function to occur. Chronic exposure to PI3Ki may in some contexts reduce the magnitude of effector lymphocytes and humoral responses generated and potentially impact the quantity and quality of immune memory (Fig. 1B). However, based on beneficial impact on CD8 memory responses that have been observed in some tumor models, it remains possible that PI3Ki treatment with appropriate timing and duration may in fact preserve “stemness” properties during T cell differentiation and avoid excessive terminal differentiation and exhaustion during infections.

We propose that future exploration of PI3Ki therapy for infectious disease should focus on their application within a short window of time during the acute phase of the infection. The purpose of the treatment would be to stimulate beneficial innate responses needed for acute disease control while concurrently restricting the suppressive regulatory responses. Discontinuation of treatment after the acute phase would allow unfettered development of adaptive immune responses and development of lymphocyte effector cells needed for final pathogen clearance. Optimizing the dose of PI3Ki drugs will also be important to avoid either excessive immune/inflammatory pathology during the acute phase or impaired adaptive immunity.

Given the established clinical use of this class of drugs in oncology and their clear immune regulatory potential, the proposed repurposing could provide a unique new tool in the arsenal for managing some difficult-to-treat infectious diseases. Although the most evidence is currently available for PI3Kδi, it is unclear whether dual targeting of PI3Kδ and other isoforms, such as PI3Kα or PI3Kγ, will improve therapeutic benefit or increase undesirable immune-suppressive effects in the context of infectious diseases. In addition to long-term immune-suppressive effects, another potential risk associated with PI3Ki is exacerbation of systemic inflammation, or cytokine storm, during the acute stage of infection. Although this has not been observed in animal models to date, it would certainly be a major consideration for some infectious diseases such as COVID-19. As for all immunotherapies, the balance between protective and pathologic responses is an important issue that might be manageable with optimized timing, dose, and selectivity of the treatment. There is minimal evidence to suggest that single isoform inhibitors, such as PI3Kδi, increase the risks of infection in cancer patients; instead, available data show that significantly higher risks are encountered with the use of multikinase inhibitors or when in combination with cytotoxic chemotherapeutic agents in cancer patients (133). It remains possible that in the context of acute treatment for infections versus the chronic treatment of cancer patients, toxicities of PI3Ki targeting multiple isoforms may be less of an issue.

Significant gaps in our knowledge regarding immune regulatory roles of PI3Ks in infectious disease need to be filled. A pertinent gap is identifying the spectrum of infectious disease agents in which PI3Ki would be most applicable and effective. The currently available data do not comprehensively address all infectious disease contexts, and thus, general conclusions about potential use of PI3Ki for different classes of pathogens cannot be drawn at this time. PI3Ki treatment studies in different infection models, particularly viral infections in which evidence is currently very limited, would help in drawing conclusions on the similarities shared by the organisms exhibiting beneficial responses. Identifying the specific mechanisms by which PI3Ki can restrict replication of some intracellular pathogens will be informative. Given the importance of innate lymphoid cells in controlling early innate responses, it will also be important to understand the impact of PI3Ki on these innate cells. If fully understood, this holistic view would further lay the foundation for the use of PI kinase inhibitors as therapeutics in infectious diseases as we collectively continue to wage the war against microbial invaders worldwide.

We thank Dr. Klaus Okkenhaug and Dr. Jude Uzonna for critical reading of the manuscript.

This work was supported by Canadian Institutes for Health Research Grant PJT-162268 (to A.J.M.). F.A. was supported by a studentship from Research Manitoba.

Abbreviations used in this article:

APDS

activated PI3Kδ syndrome

Breg

regulatory B cell

CLL

chronic lymphocytic leukemia

GC

germinal center

GOF

gain-of-function

LOF

loss-of-function

PI

phosphoinositide

PI3K

phosphoinositide 3-kinase

PI3Ki

PI3K inhibitor

PI3Kδi

PI3Kδ inhibitor

TFH

follicular helper T cell

Treg

regulatory T cell.

1
Foster
,
F. M.
,
C. J.
Traer
,
S. M.
Abraham
,
M. J.
Fry
.
2003
.
The phosphoinositide (PI) 3-kinase family.
J. Cell Sci.
116
:
3037
3040
.
2
Vanhaesebroeck
,
B.
,
L.
Stephens
,
P.
Hawkins
.
2012
.
PI3K signalling: the path to discovery and understanding.
Nat. Rev. Mol. Cell Biol.
13
:
195
203
.
3
Arcaro
,
A.
,
M. P.
Wymann
.
1993
.
Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses.
Biochem. J.
296
:
297
301
.
4
Vlahos
,
C. J.
,
W. F.
Matter
,
K. Y.
Hui
,
R. F.
Brown
.
1994
.
A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).
J. Biol. Chem.
269
:
5241
5248
.
5
Stark
,
A.-K.
,
S.
Sriskantharajah
,
E. M.
Hessel
,
K.
Okkenhaug
.
2015
.
PI3K inhibitors in inflammation, autoimmunity and cancer.
Curr. Opin. Pharmacol.
23
:
82
91
.
6
Gopal
,
A. K.
,
B. S.
Kahl
,
S.
de Vos
,
N. D.
Wagner-Johnston
,
S. J.
Schuster
,
W. J.
Jurczak
,
I. W.
Flinn
,
C. R.
Flowers
,
P.
Martin
,
A.
Viardot
, et al
.
2014
.
PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma.
N. Engl. J. Med.
370
:
1008
1018
.
7
Furman
,
R. R.
,
J. P.
Sharman
,
S. E.
Coutre
,
B. D.
Cheson
,
J. M.
Pagel
,
P.
Hillmen
,
J. C.
Barrientos
,
A. D.
Zelenetz
,
T. J.
Kipps
,
I.
Flinn
, et al
.
2014
.
Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.
N. Engl. J. Med.
370
:
997
1007
.
8
Flinn
,
I. W.
,
P.
Hillmen
,
M.
Montillo
,
Z.
Nagy
,
Á.
Illés
,
G.
Etienne
,
J.
Delgado
,
B. J.
Kuss
,
C. S.
Tam
,
Z.
Gasztonyi
, et al
.
2018
.
The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL.
Blood
132
:
2446
2455
.
9
Dreyling
,
M.
,
A.
Santoro
,
L.
Mollica
,
S.
Leppä
,
G.
Follows
,
G.
Lenz
,
W. S.
Kim
,
A.
Nagler
,
M.
Dimou
,
J.
Demeter
, et al
.
2019
.
Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study.
Am. J. Hematol.
DOI:.
10
André
,
F.
,
E.
Ciruelos
,
G.
Rubovszky
,
M.
Campone
,
S.
Loibl
,
H. S.
Rugo
,
H.
Iwata
,
P.
Conte
,
I. A.
Mayer
,
B.
Kaufman
, et al
SOLAR-1 Study Group
.
2019
.
Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer.
N. Engl. J. Med.
380
:
1929
1940
.
11
Hawkins
,
P. T.
,
L. R.
Stephens
.
2015
.
PI3K signalling in inflammation.
Biochim Biophys Acta
1851
:
882
897
.
12
Cantley
,
L. C.
2002
.
The phosphoinositide 3-kinase pathway.
Science
296
:
1655
1657
.
13
Salamon
,
R. S.
,
J. M.
Backer
.
2013
.
Phosphatidylinositol-3,4,5-trisphosphate: tool of choice for class I PI 3-kinases.
Bioessays
35
:
602
611
.
14
Hawkins
,
P. T.
,
L. R.
Stephens
.
2016
.
Emerging evidence of signalling roles for PI(3,4)P2 in Class I and II PI3K-regulated pathways.
Biochem. Soc. Trans.
44
:
307
314
.
15
Li
,
H.
,
A. J.
Marshall
.
2015
.
Phosphatidylinositol (3,4) bisphosphate-specific phosphatases and effector proteins: a distinct branch of PI3K signaling.
Cell. Signal.
27
:
1789
1798
.
16
Okkenhaug
,
K.
2013
.
Rules of engagement: distinct functions for the four class I PI3K catalytic isoforms in immunity.
Ann. N. Y. Acad. Sci.
1280
:
24
26
.
17
Pal Singh
,
S.
,
F.
Dammeijer
,
R. W.
Hendriks
.
2018
.
Role of Bruton’s tyrosine kinase in B cells and malignancies. [Published erratum appears in 2019 Mol. Cancer 18: 79.]
Mol. Cancer
17
:
57
.
18
Rawlings
,
D. J.
,
O. N.
Witte
.
1995
.
The Btk subfamily of cytoplasmic tyrosine kinases: structure, regulation and function.
Semin. Immunol.
7
:
237
246
.
19
Manning
,
B. D.
,
A.
Toker
.
2017
.
AKT/PKB signaling: navigating the network.
Cell
169
:
381
405
.
20
Dan
,
H. C.
,
R. J.
Antonia
,
A. S.
Baldwin
.
2016
.
PI3K/Akt promotes feedforward mTORC2 activation through IKKα.
Oncotarget
7
:
21064
21075
.
21
Gan
,
X.
,
J.
Wang
,
B.
Su
,
D.
Wu
.
2011
.
Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate.
J. Biol. Chem.
286
:
10998
11002
.
22
Lemmon
,
M. A.
2007
.
Pleckstrin homology (PH) domains and phosphoinositides.
Biochem. Soc. Symp.
81
93
.
23
Zhang
,
T. T.
,
H.
Li
,
S. M.
Cheung
,
J. L.
Costantini
,
S.
Hou
,
M.
Al-Alwan
,
A. J.
Marshall
.
2009
.
Phosphoinositide 3-kinase-regulated adapters in lymphocyte activation.
Immunol. Rev.
232
:
255
272
.
24
Okkenhaug
,
K.
,
A.
Bilancio
,
G.
Farjot
,
H.
Priddle
,
S.
Sancho
,
E.
Peskett
,
W.
Pearce
,
S. E.
Meek
,
A.
Salpekar
,
M. D.
Waterfield
, et al
.
2002
.
Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice.
Science
297
:
1031
1034
.
25
Jayachandran
,
N.
,
E. M.
Mejia
,
K.
Sheikholeslami
,
A. A.
Sher
,
S.
Hou
,
G. M.
Hatch
,
A. J.
Marshall
.
2018
.
TAPP adaptors control B cell metabolism by modulating the phosphatidylinositol 3-kinase signaling pathway: a novel regulatory circuit preventing autoimmunity.
J. Immunol.
201
:
406
416
.
26
Saudemont
,
A.
,
F.
Colucci
.
2009
.
PI3K signaling in lymphocyte migration.
Cell Cycle
8
:
3307
3310
.
27
Ali
,
A. Y.
,
X.
Wu
,
N.
Eissa
,
S.
Hou
,
J.-E.
Ghia
,
T. T.
Murooka
,
V.
Banerji
,
J. B.
Johnston
,
F.
Lin
,
S. B.
Gibson
,
A. J.
Marshall
.
2018
.
Distinct roles for phosphoinositide 3-kinases γ and δ in malignant B cell migration.
Leukemia
32
:
1958
1969
.
28
Koyasu
,
S.
2003
.
The role of PI3K in immune cells.
Nat. Immunol.
4
:
313
319
.
29
Pauls
,
S. D.
,
S. T.
Lafarge
,
I.
Landego
,
T.
Zhang
,
A. J.
Marshall
.
2012
.
The phosphoinositide 3-kinase signaling pathway in normal and malignant B cells: activation mechanisms, regulation and impact on cellular functions.
Front. Immunol.
3
:
224
.
30
Pauls
,
S. D.
,
A. J.
Marshall
.
2017
.
Regulation of immune cell signaling by SHIP1: a phosphatase, scaffold protein, and potential therapeutic target.
Eur. J. Immunol.
47
:
932
945
.
31
Martini
,
M.
,
M. C.
De Santis
,
L.
Braccini
,
F.
Gulluni
,
E.
Hirsch
.
2014
.
PI3K/AKT signaling pathway and cancer: an updated review.
Ann. Med.
46
:
372
383
.
32
Wang
,
Q.
,
Y. L.
Shi
,
K.
Zhou
,
L. L.
Wang
,
Z. X.
Yan
,
Y. L.
Liu
,
L. L.
Xu
,
S. W.
Zhao
,
H. L.
Chu
,
T. T.
Shi
, et al
.
2018
.
PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer.
Cell Death Dis.
9
:
739
.
33
Waniczek
,
D.
,
M.
Śnietura
,
Z.
Lorenc
,
E.
Nowakowska-Zajdel
,
M.
Muc-Wierzgoń
.
2018
.
Assessment of PI3K/AKT/PTEN signaling pathway activity in colorectal cancer using quantum dot-conjugated antibodies.
Oncol. Lett.
15
:
1236
1240
.
34
Verret
,
B.
,
J.
Cortes
,
T.
Bachelot
,
F.
Andre
,
M.
Arnedos
.
2019
.
Efficacy of PI3K inhibitors in advanced breast cancer.
Ann. Oncol.
30
:
x12
x20
.
35
Okkenhaug
,
K.
,
J. A.
Burger
.
2016
.
PI3K signaling in normal B cells and chronic lymphocytic leukemia (CLL).
Curr. Top. Microbiol. Immunol.
393
:
123
142
.
36
Yang
,
J.
,
J.
Nie
,
X.
Ma
,
Y.
Wei
,
Y.
Peng
,
X.
Wei
.
2019
.
Targeting PI3K in cancer: mechanisms and advances in clinical trials.
Mol. Cancer
18
:
26
.
37
Fruman
,
D. A.
,
H.
Chiu
,
B. D.
Hopkins
,
S.
Bagrodia
,
L. C.
Cantley
,
R. T.
Abraham
.
2017
.
The PI3K pathway in human disease.
Cell
170
:
605
635
.
38
Fruman
,
D. A.
,
L. C.
Cantley
.
2014
.
Idelalisib--a PI3Kδ inhibitor for B-cell cancers.
N. Engl. J. Med.
370
:
1061
1062
.
39
Vangapandu
,
H. V.
,
N.
Jain
,
V.
Gandhi
.
2017
.
Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia.
Expert Opin. Investig. Drugs
26
:
625
632
.
40
Krause
,
G.
,
F.
Hassenrück
,
M.
Hallek
.
2018
.
Copanlisib for treatment of B-cell malignancies: the development of a PI3K inhibitor with considerable differences to idelalisib.
Drug Des. Devel. Ther.
12
:
2577
2590
.
41
Ito
,
K.
,
G.
Caramori
,
I. M.
Adcock
.
2007
.
Therapeutic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease.
J. Pharmacol. Exp. Ther.
321
:
1
8
.
42
Banham-Hall
,
E.
,
M. R.
Clatworthy
,
K.
Okkenhaug
.
2012
.
The therapeutic potential for PI3K inhibitors in autoimmune rheumatic diseases.
Open Rheumatol. J.
6
:
245
258
.
43
Puri
,
K. D.
,
M. R.
Gold
.
2012
.
Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies.
Front. Immunol.
3
:
256
.
44
Greaves
,
S. A.
,
J. N.
Peterson
,
P.
Strauch
,
R. M.
Torres
,
R.
Pelanda
.
2019
.
Active PI3K abrogates central tolerance in high-avidity autoreactive B cells.
J. Exp. Med.
216
:
1135
1153
.
45
Browne
,
C. D.
,
C. J.
Del Nagro
,
M. H.
Cato
,
H. S.
Dengler
,
R. C.
Rickert
.
2009
.
Suppression of phosphatidylinositol 3,4,5-trisphosphate production is a key determinant of B cell anergy.
Immunity
31
:
749
760
.
46
Franks
,
S. E.
,
A.
Getahun
,
J. C.
Cambier
.
2019
.
A precision B cell-targeted therapeutic approach to autoimmunity caused by phosphatidylinositol 3-kinase pathway dysregulation.
J. Immunol.
202
:
3381
3393
.
47
Southworth
,
T.
,
J.
Plumb
,
V.
Gupta
,
J.
Pearson
,
I.
Ramis
,
M. D.
Lehner
,
M.
Miralpeix
,
D.
Singh
.
2016
.
Anti-inflammatory potential of PI3Kδ and JAK inhibitors in asthma patients.
Respir. Res.
17
:
124
.
48
Lee
,
K. S.
,
H. K.
Lee
,
J. S.
Hayflick
,
Y. C.
Lee
,
K. D.
Puri
.
2006
.
Inhibition of phosphoinositide 3-kinase δ attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model.
FASEB J.
20
:
455
465
.
49
Horiguchi
,
M.
,
Y.
Oiso
,
H.
Sakai
,
T.
Motomura
,
C.
Yamashita
.
2015
.
Pulmonary administration of phosphoinositide 3-kinase inhibitor is a curative treatment for chronic obstructive pulmonary disease by alveolar regeneration.
J. Control. Release
213
:
112
119
.
50
Pirozzi
,
F.
,
K.
Ren
,
A.
Murabito
,
A.
Ghigo
.
2019
.
PI3K signaling in chronic obstructive pulmonary disease: mechanisms, targets, and therapy.
Curr. Med. Chem.
26
:
2791
2800
.
51
Camps
,
M.
,
T.
Rückle
,
H.
Ji
,
V.
Ardissone
,
F.
Rintelen
,
J.
Shaw
,
C.
Ferrandi
,
C.
Chabert
,
C.
Gillieron
,
B.
Françon
, et al
.
2005
.
Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis.
Nat. Med.
11
:
936
943
.
52
Wang
,
Y.
,
L.
Zhang
,
P.
Wei
,
H.
Zhang
,
C.
Liu
.
2014
.
Inhibition of PI3Kδ improves systemic lupus in mice.
Inflammation
37
:
978
983
.
53
Toro-Domínguez
,
D.
,
P.
Carmona-Sáez
,
M. E.
Alarcón-Riquelme
.
2017
.
Support for phosphoinositol 3 kinase and mTOR inhibitors as treatment for lupus using in-silico drug-repurposing analysis.
Arthritis Res. Ther.
19
:
54
.
54
Cahn
,
A.
,
J. N.
Hamblin
,
M.
Begg
,
R.
Wilson
,
L.
Dunsire
,
S.
Sriskantharajah
,
M.
Montembault
,
C. N.
Leemereise
,
L.
Galinanes-Garcia
,
H.
Watz
, et al
.
2017
.
Safety, pharmacokinetics and dose-response characteristics of GSK2269557, an inhaled PI3Kδ inhibitor under development for the treatment of COPD.
Pulm. Pharmacol. Ther.
46
:
69
77
.
55
Jou
,
S.-T.
,
N.
Carpino
,
Y.
Takahashi
,
R.
Piekorz
,
J.-R.
Chao
,
N.
Carpino
,
D.
Wang
,
J. N.
Ihle
.
2002
.
Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the B-cell receptor complex.
Mol. Cell. Biol.
22
:
8580
8591
.
56
Clayton
,
E.
,
G.
Bardi
,
S. E.
Bell
,
D.
Chantry
,
C. P.
Downes
,
A.
Gray
,
L. A.
Humphries
,
D.
Rawlings
,
H.
Reynolds
,
E.
Vigorito
,
M.
Turner
.
2002
.
A crucial role for the p110δ subunit of phosphatidylinositol 3-kinase in B cell development and activation.
J. Exp. Med.
196
:
753
763
.
57
Patton
,
D. T.
,
O. A.
Garden
,
W. P.
Pearce
,
L. E.
Clough
,
C. R.
Monk
,
E.
Leung
,
W. C.
Rowan
,
S.
Sancho
,
L. S. K.
Walker
,
B.
Vanhaesebroeck
,
K.
Okkenhaug
.
2006
.
Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells.
J. Immunol.
177
:
6598
6602
.
58
Sogkas
,
G.
,
M.
Fedchenko
,
A.
Dhingra
,
A.
Jablonka
,
R. E.
Schmidt
,
F.
Atschekzei
.
2018
.
Primary immunodeficiency disorder caused by phosphoinositide 3-kinase δ deficiency.
J. Allergy Clin. Immunol.
142
:
1650
1653.e2
.
59
Swan
,
D. J.
,
D.
Aschenbrenner
,
C. A.
Lamb
,
K.
Chakraborty
,
J.
Clark
,
S.
Pandey
,
K. R.
Engelhardt
,
R.
Chen
,
A.
Cavounidis
,
Y.
Ding
, et al
.
2019
.
Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ.
Haematologica
104
:
e483
e486
.
60
Kaneda
,
M. M.
,
K. S.
Messer
,
N.
Ralainirina
,
H.
Li
,
C. J.
Leem
,
S.
Gorjestani
,
G.
Woo
,
A. V.
Nguyen
,
C. C.
Figueiredo
,
P.
Foubert
, et al
.
2016
.
PI3Kγ is a molecular switch that controls immune suppression. [Published erratum appears in 2017 Nature 542: 124.]
Nature
539
:
437
442
.
61
Sasaki
,
T.
,
J.
Irie-Sasaki
,
R. G.
Jones
,
A. J.
Oliveira-dos-Santos
,
W. L.
Stanford
,
B.
Bolon
,
A.
Wakeham
,
A.
Itie
,
D.
Bouchard
,
I.
Kozieradzki
, et al
.
2000
.
Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration.
Science
287
:
1040
1046
.
62
Ladygina
,
N.
,
S.
Gottipati
,
K.
Ngo
,
G.
Castro
,
J.-Y.
Ma
,
H.
Banie
,
T. S.
Rao
,
W.-P.
Fung-Leung
.
2013
.
PI3Kγ kinase activity is required for optimal T-cell activation and differentiation.
Eur. J. Immunol.
43
:
3183
3196
.
63
Ji
,
H.
,
F.
Rintelen
,
C.
Waltzinger
,
D.
Bertschy Meier
,
A.
Bilancio
,
W.
Pearce
,
E.
Hirsch
,
M. P.
Wymann
,
T.
Rückle
,
M.
Camps
, et al
.
2007
.
Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation.
Blood
110
:
2940
2947
.
64
Takeda
,
A. J.
,
T. J.
Maher
,
Y.
Zhang
,
S. M.
Lanahan
,
M. L.
Bucklin
,
S. R.
Compton
,
P. M.
Tyler
,
W. A.
Comrie
,
M.
Matsuda
,
K. N.
Olivier
, et al
.
2019
.
Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.
Nat. Commun.
10
:
4364
.
65
Takeda
,
A. J.
,
Y.
Zhang
,
G. L.
Dornan
,
B. D.
Siempelkamp
,
M. L.
Jenkins
,
H. F.
Matthews
,
J. J.
McElwee
,
W.
Bi
,
F. O.
Seeborg
,
H. C.
Su
, et al
.
2017
.
Novel PIK3CD mutations affecting N-terminal residues of p110δ cause activated PI3Kδ syndrome (APDS) in humans.
J. Allergy Clin. Immunol.
140
:
1152
1156.e10
.
66
Walsh
,
C. M.
,
D. A.
Fruman
.
2014
.
Too much of a good thing: immunodeficiency due to hyperactive PI3K signaling.
J. Clin. Invest.
124
:
3688
3690
.
67
Angulo
,
I.
,
O.
Vadas
,
F.
Garçon
,
E.
Banham-Hall
,
V.
Plagnol
,
T. R.
Leahy
,
H.
Baxendale
,
T.
Coulter
,
J.
Curtis
,
C.
Wu
, et al
.
2013
.
Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.
Science
342
:
866
871
.
68
Lucas
,
C. L.
,
H. S.
Kuehn
,
F.
Zhao
,
J. E.
Niemela
,
E. K.
Deenick
,
U.
Palendira
,
D. T.
Avery
,
L.
Moens
,
J. L.
Cannons
,
M.
Biancalana
, et al
.
2014
.
Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency.
Nat. Immunol.
15
:
88
97
.
69
Asano
,
T.
,
S.
Okada
,
M.
Tsumura
,
T.-W.
Yeh
,
K.
Mitsui-Sekinaka
,
Y.
Tsujita
,
Y.
Ichinose
,
A.
Shimada
,
K.
Hashimoto
,
T.
Wada
, et al
.
2018
.
Enhanced AKT phosphorylation of circulating B cells in patients with activated PI3Kδ syndrome.
Front. Immunol.
9
:
568
.
70
Baleydier
,
F.
,
E.
Ranza
,
M.
Schäppi
,
A.-L.
Rougemont
,
L.
Merlini
,
M.
Ansari
,
G.
Blanchard-Rohner
.
2019
.
Activated phosphoinositide 3 kinase delta syndrome (APDS): a primary immunodeficiency mimicking lymphoma.
J. Pediatr. Hematol. Oncol.
41
:
e521
e524
.
71
Wray-Dutra
,
M. N.
,
F.
Al Qureshah
,
G.
Metzler
,
M.
Oukka
,
R. G.
James
,
D. J.
Rawlings
.
2018
.
Activated PIK3CD drives innate B cell expansion yet limits B cell-intrinsic immune responses.
J. Exp. Med.
215
:
2485
2496
.
72
Avery
,
D. T.
,
A.
Kane
,
T.
Nguyen
,
A.
Lau
,
A.
Nguyen
,
H.
Lenthall
,
K.
Payne
,
W.
Shi
,
H.
Brigden
,
E.
French
, et al
.
2018
.
Germline-activating mutations in PIK3CD compromise B cell development and function.
J. Exp. Med.
215
:
2073
2095
.
73
Preite
,
S.
,
J. L.
Cannons
,
A. J.
Radtke
,
I.
Vujkovic-Cvijin
,
J.
Gomez-Rodriguez
,
S.
Volpi
,
B.
Huang
,
J.
Cheng
,
N.
Collins
,
J.
Reilley
, et al
.
2018
.
Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity.
Nat. Immunol.
19
:
986
1000
.
74
Stark
,
A.-K.
,
A.
Chandra
,
K.
Chakraborty
,
R.
Alam
,
V.
Carbonaro
,
J.
Clark
,
S.
Sriskantharajah
,
G.
Bradley
,
A. G.
Richter
,
E.
Banham-Hall
, et al
.
2018
.
PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner.
Nat. Commun.
9
:
3174
.
75
Preite
,
S.
,
J.
Gomez-Rodriguez
,
J. L.
Cannons
,
P. L.
Schwartzberg
.
2019
.
T and B-cell signaling in activated PI3K delta syndrome: from immunodeficiency to autoimmunity.
Immunol. Rev.
291
:
154
173
.
76
Narayan
,
N.
,
P.
Hewins
,
P.
Lane
,
B.
Rhodes
.
2018
.
47. Activated PI3 kinase delta syndrome: a rare cause of inflammatory disease.
Rheumatol. Adv. Pract.
2
:
rky034.010
. Available at: .
77
Elkaim
,
E.
,
B.
Neven
,
J.
Bruneau
,
K.
Mitsui-Sekinaka
,
A.
Stanislas
,
L.
Heurtier
,
C. L.
Lucas
,
H.
Matthews
,
M.-C.
Deau
,
S.
Sharapova
, et al
.
2016
.
Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study.
J. Allergy Clin. Immunol.
138
:
210
218.e9
.
78
Coulter
,
T. I.
,
A.
Chandra
,
C. M.
Bacon
,
J.
Babar
,
J.
Curtis
,
N.
Screaton
,
J. R.
Goodlad
,
G.
Farmer
,
C. L.
Steele
,
T. R.
Leahy
, et al
.
2017
.
Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.
J. Allergy Clin. Immunol.
139
:
597
606.e4
.
79
Condliffe
,
A. M.
,
A.
Chandra
.
2018
.
Respiratory manifestations of the activated phosphoinositide 3-kinase delta syndrome.
Front. Immunol.
9
:
338
.
80
Edwards
,
E. S. J.
,
J.
Bier
,
T. S.
Cole
,
M.
Wong
,
P.
Hsu
,
L. J.
Berglund
,
K.
Boztug
,
A.
Lau
,
E.
Gostick
,
D. A.
Price
, et al
.
2019
.
Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity.
J. Allergy Clin. Immunol.
143
:
276
291.e6
.
81
Karanovic
,
D.
,
I. C.
Michelow
,
A. R.
Hayward
,
S. S.
DeRavin
,
O. M.
Delmonte
,
M. E.
Grigg
,
A. K.
Dobbs
,
J. E.
Niemela
,
J.
Stoddard
,
Z.
Alhinai
, et al
.
2019
.
Disseminated and congenital toxoplasmosis in a mother and child with activated PI3-kinase δ syndrome type 2 (APDS2): case report and a literature review of Toxoplasma infections in primary immunodeficiencies.
Front. Immunol.
10
:
77
.
82
Rao
,
V. K.
,
S.
Webster
,
V. A. S. H.
Dalm
,
A.
Šedivá
,
P. M.
van Hagen
,
S.
Holland
,
S. D.
Rosenzweig
,
A. D.
Christ
,
B.
Sloth
,
M.
Cabanski
, et al
.
2017
.
Effective “activated PI3Kδ syndrome”-targeted therapy with the PI3Kδ inhibitor leniolisib.
Blood
130
:
2307
2316
.
83
World Health Organization
. 2018. Fact sheet: top 10 causes of death.
World Health Organization
,
Geneva, Switzerland
. Available at: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death. Accessed: April 21, 2020.
84
Chugh
,
P.
,
B.
Bradel-Tretheway
,
C. M. R.
Monteiro-Filho
,
V.
Planelles
,
S. B.
Maggirwar
,
S.
Dewhurst
,
B.
Kim
.
2008
.
Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy.
Retrovirology
5
:
11
.
85
Campbell
,
G. R.
,
R. S.
Bruckman
,
S. D.
Herns
,
S.
Joshi
,
D. L.
Durden
,
S. A.
Spector
.
2018
.
Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication.
J. Biol. Chem.
293
:
5808
5820
.
86
Li
,
H.
,
J.
Zhu
,
M.
He
,
Q.
Luo
,
F.
Liu
,
R.
Chen
.
2018
.
Marek’s disease virus activates the PI3K/Akt pathway through interaction of its protein meq with the P85 subunit of PI3K to promote viral replication.
Front. Microbiol.
9
:
2547
.
87
Kindrachuk
,
J.
,
B.
Ork
,
B. J.
Hart
,
S.
Mazur
,
M. R.
Holbrook
,
M. B.
Frieman
,
D.
Traynor
,
R. F.
Johnson
,
J.
Dyall
,
J. H.
Kuhn
, et al
.
2015
.
Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis.
Antimicrob. Agents Chemother.
59
:
1088
1099
.
88
Zhou
,
W.
,
J.-H.
Quan
,
Y.-H.
Lee
,
D.-W.
Shin
,
G.-H.
Cha
.
2013
.
Toxoplasma gondii proliferation require down-regulation of host Nox4 expression via activation of PI3 kinase/Akt signaling pathway.
PLoS One
8
: e66306.
89
Chen
,
X.-M.
,
P. L.
Splinter
,
P. S.
Tietz
,
B. Q.
Huang
,
D. D.
Billadeau
,
N. F.
LaRusso
.
2004
.
Phosphatidylinositol 3-kinase and frabin mediate Cryptosporidium parvum cellular invasion via activation of Cdc42.
J. Biol. Chem.
279
:
31671
31678
.
90
Huang
,
G.
,
G.
Redelman-Sidi
,
N.
Rosen
,
M. S.
Glickman
,
X.
Jiang
.
2012
.
Inhibition of mycobacterial infection by the tumor suppressor PTEN.
J. Biol. Chem.
287
:
23196
23202
.
91
Rosenthal
,
K. L.
2006
.
Tweaking innate immunity: the promise of innate immunologicals as anti-infectives.
Can. J. Infect. Dis. Med. Microbiol.
17
:
307
314
.
92
Jain
,
A.
,
C.
Pasare
.
2017
.
Innate control of adaptive immunity: beyond the three-signal paradigm.
J. Immunol.
198
:
3791
3800
.
93
Fan
,
W.
,
H.
Morinaga
,
J. J.
Kim
,
E.
Bae
,
N. J.
Spann
,
S.
Heinz
,
C. K.
Glass
,
J. M.
Olefsky
.
2010
.
FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages.
EMBO J.
29
:
4223
4236
.
94
Aksoy
,
E.
,
W.
Vanden Berghe
,
S.
Detienne
,
Z.
Amraoui
,
K. A.
Fitzgerald
,
G.
Haegeman
,
M.
Goldman
,
F.
Willems
.
2005
.
Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-kappa B activation and IFN-beta synthesis downstream of toll-like receptor 3 and 4.
Eur. J. Immunol.
35
:
2200
2209
.
95
Fukao
,
T.
,
S.
Koyasu
.
2003
.
PI3K and negative regulation of TLR signaling.
Trends Immunol.
24
:
358
363
.
96
Papakonstanti
,
E. A.
,
O.
Zwaenepoel
,
A.
Bilancio
,
E.
Burns
,
G. E.
Nock
,
B.
Houseman
,
K.
Shokat
,
A. J.
Ridley
,
B.
Vanhaesebroeck
.
2008
.
Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages.
J. Cell Sci.
121
:
4124
4133
.
97
Uno
,
J. K.
,
K. N.
Rao
,
K.
Matsuoka
,
S. Z.
Sheikh
,
T.
Kobayashi
,
F.
Li
,
E. C.
Steinbach
,
A. R.
Sepulveda
,
B.
Vanhaesebroeck
,
R. B.
Sartor
,
S. E.
Plevy
.
2010
.
Altered macrophage function contributes to colitis in mice defective in the phosphoinositide-3 kinase subunit p110δ.
Gastroenterology
139
:
1642
1653, 1653.e1–1653.e6
.
98
Vergadi
,
E.
,
E.
Ieronymaki
,
K.
Lyroni
,
K.
Vaporidi
,
C.
Tsatsanis
.
2017
.
Akt signaling pathway in macrophage activation and M1/M2 polarization.
J. Immunol.
198
:
1006
1014
.
99
Androulidaki
,
A.
,
D.
Iliopoulos
,
A.
Arranz
,
C.
Doxaki
,
S.
Schworer
,
V.
Zacharioudaki
,
A. N.
Margioris
,
P. N.
Tsichlis
,
C.
Tsatsanis
.
2009
.
The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs.
Immunity
31
:
220
231
.
100
Yu
,
Y.
,
S.
Nagai
,
H.
Wu
,
A. S.
Neish
,
S.
Koyasu
,
A. T.
Gewirtz
.
2006
.
TLR5-mediated phosphoinositide 3-kinase activation negatively regulates flagellin-induced proinflammatory gene expression.
J. Immunol.
176
:
6194
6201
.
101
Troutman
,
T. D.
,
J. F.
Bazan
,
C.
Pasare
.
2012
.
Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K.
Cell Cycle
11
:
3559
3567
.
102
Fukao
,
T.
,
M.
Tanabe
,
Y.
Terauchi
,
T.
Ota
,
S.
Matsuda
,
T.
Asano
,
T.
Kadowaki
,
T.
Takeuchi
,
S.
Koyasu
.
2002
.
PI3K-mediated negative feedback regulation of IL-12 production in DCs.
Nat. Immunol.
3
:
875
881
.
103
Dil
,
N.
,
A. J.
Marshall
.
2009
.
Role of phosphoinositide 3-kinase p110 δ in TLR4- and TLR9-mediated B cell cytokine production and differentiation.
Mol. Immunol.
46
:
1970
1978
.
104
Marshall
,
N. A.
,
K. C.
Galvin
,
A.-M. B.
Corcoran
,
L.
Boon
,
R.
Higgs
,
K. H. G.
Mills
.
2012
.
Immunotherapy with PI3K inhibitor and toll-like receptor agonist induces IFN-γ+IL-17+ polyfunctional T cells that mediate rejection of murine tumors.
Cancer Res.
72
:
581
591
.
105
Chakravortty
,
D.
,
M.
Hensel
.
2003
.
Inducible nitric oxide synthase and control of intracellular bacterial pathogens.
Microbes Infect.
5
:
621
627
.
106
Sullivan
,
R. J.
,
D. S.
Hong
,
A. W.
Tolcher
,
A.
Patnaik
,
G.
Shapiro
,
B.
Chmielowski
,
A.
Ribas
,
L. H.
Brail
,
J.
Roberts
,
L.
Lee
, et al
.
2018
.
Initial results from first-in-human study of IPI-549, a tumor macrophage-targeting agent, combined with nivolumab in advanced solid tumors.
JCO
36
(
15_suppl
):
3013
3013
.
107
Luyendyk
,
J. P.
,
G. A.
Schabbauer
,
M.
Tencati
,
T.
Holscher
,
R.
Pawlinski
,
N.
Mackman
.
2008
.
Genetic analysis of the role of the PI3K-Akt pathway in lipopolysaccharide-induced cytokine and tissue factor gene expression in monocytes/macrophages.
J. Immunol.
180
:
4218
4226
.
108
Kuroda
,
S.
,
M.
Nishio
,
T.
Sasaki
,
Y.
Horie
,
K.
Kawahara
,
M.
Sasaki
,
M.
Natsui
,
T.
Matozaki
,
H.
Tezuka
,
T.
Ohteki
, et al
.
2008
.
Effective clearance of intracellular Leishmania major in vivo requires Pten in macrophages.
Eur. J. Immunol.
38
:
1331
1340
.
109
Fujita
,
A.
,
K.
Kan-O
,
K.
Tonai
,
N.
Yamamoto
,
T.
Ogawa
,
S.
Fukuyama
,
Y.
Nakanishi
,
K.
Matsumoto
.
2020
.
Inhibition of PI3Kδ enhances poly I:C-induced antiviral responses and inhibits replication of human metapneumovirus in murine lungs and human bronchial epithelial cells.
Front. Immunol.
11
:
432
.
110
Chellappa
,
S.
,
K.
Kushekhar
,
L. A.
Munthe
,
G. E.
Tjønnfjord
,
E. M.
Aandahl
,
K.
Okkenhaug
,
K.
Taskén
.
2019
.
The PI3K p110δ isoform inhibitor idelalisib preferentially inhibits human regulatory T cell function.
J. Immunol.
202
:
1397
1405
.
111
Ali
,
K.
,
D. R.
Soond
,
R.
Pineiro
,
T.
Hagemann
,
W.
Pearce
,
E. L.
Lim
,
H.
Bouabe
,
C. L.
Scudamore
,
T.
Hancox
,
H.
Maecker
, et al
.
2014
.
Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. [Published erratum appears in 2016 Nature 535: 580.]
Nature
510
:
407
411
.
112
Lim
,
E. L.
,
F. M.
Cugliandolo
,
D. R.
Rosner
,
D.
Gyori
,
R.
Roychoudhuri
,
K.
Okkenhaug
.
2018
.
Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors.
JCI Insight
3
: e120626.
113
Lim
,
E. L.
,
K.
Okkenhaug
.
2019
.
Phosphoinositide 3-kinase δ is a regulatory T-cell target in cancer immunotherapy.
Immunology
157
:
210
218
.
114
Taylor
,
A.
,
J.
Verhagen
,
K.
Blaser
,
M.
Akdis
,
C. A.
Akdis
.
2006
.
Mechanisms of immune suppression by interleukin-10 and transforming growth factor-β: the role of T regulatory cells.
Immunology
117
:
433
442
.
115
Liu
,
D.
,
T.
Zhang
,
A. J.
Marshall
,
K.
Okkenhaug
,
B.
Vanhaesebroeck
,
J. E.
Uzonna
.
2009
.
The p110δ isoform of phosphatidylinositol 3-kinase controls susceptibility to Leishmania major by regulating expansion and tissue homing of regulatory T cells.
J. Immunol.
183
:
1921
1933
.
116
Khadem
,
F.
,
P.
Jia
,
Z.
Mou
,
A.
Feiz Barazandeh
,
D.
Liu
,
Y.
Keynan
,
J. E.
Uzonna
.
2017
.
Pharmacological inhibition of p110δ subunit of PI3K confers protection against experimental leishmaniasis.
J. Antimicrob. Chemother.
72
:
467
477
.
117
Pearce
,
V. Q.
,
H.
Bouabe
,
A. R.
MacQueen
,
V.
Carbonaro
,
K.
Okkenhaug
.
2015
.
PI3Kδ regulates the magnitude of CD8+ T cell responses after challenge with Listeria monocytogenes.
J. Immunol.
195
:
3206
3217
.
118
Zenewicz
,
L. A.
,
H.
Shen
.
2007
.
Innate and adaptive immune responses to Listeria monocytogenes: a short overview.
Microbes Infect.
9
:
1208
1215
.
119
Okkenhaug
,
K.
,
B.
Vanhaesebroeck
.
2003
.
PI3K-signalling in B- and T-cells: insights from gene-targeted mice.
Biochem. Soc. Trans.
31
:
270
274
.
120
Zhang
,
X.
2013
.
Regulatory functions of innate-like B cells.
Cell. Mol. Immunol.
10
:
113
121
.
121
O’Garra
,
A.
,
R.
Chang
,
N.
Go
,
R.
Hastings
,
G.
Haughton
,
M.
Howard
.
1992
.
Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10.
Eur. J. Immunol.
22
:
711
717
.
122
Blair
,
P. A.
,
L. Y.
Noreña
,
F.
Flores-Borja
,
D. J.
Rawlings
,
D. A.
Isenberg
,
M. R.
Ehrenstein
,
C.
Mauri
.
2010
.
CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients.
Immunity
32
:
129
140
.
123
Singh
,
A.
,
V.
Joshi
,
A. K.
Jindal
,
B.
Mathew
,
A.
Rawat
.
2019
.
An updated review on activated PI3 kinase delta syndrome (APDS).
Genes Dis.
7
:
67
74
.
124
Guilliams
,
M.
,
G.
Oldenhove
,
W.
Noel
,
M.
Hérin
,
L.
Brys
,
P.
Loi
,
V.
Flamand
,
M.
Moser
,
P.
De Baetselier
,
A.
Beschin
.
2007
.
African trypanosomiasis: naturally occurring regulatory T cells favor trypanotolerance by limiting pathology associated with sustained type 1 inflammation.
J. Immunol.
179
:
2748
2757
.
125
Patton
,
D. T.
,
F.
Garçon
,
K.
Okkenhaug
.
2007
.
The PI3K p110δ controls T-cell development, differentiation and regulation.
Biochem. Soc. Trans.
35
:
167
171
.
126
Okkenhaug
,
K.
,
D. T.
Patton
,
A.
Bilancio
,
F.
Garçon
,
W. C.
Rowan
,
B.
Vanhaesebroeck
.
2006
.
The p110δ isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells.
J. Immunol.
177
:
5122
5128
.
127
Cannons
,
J. L.
,
S.
Preite
,
S. M.
Kapnick
,
G.
Uzel
,
P. L.
Schwartzberg
.
2018
.
Genetic defects in phosphoinositide 3-kinase δ influence CD8+ T cell survival, differentiation, and function.
Front. Immunol.
9
:
1758
.
128
Gracias
,
D. T.
,
A. C.
Boesteanu
,
J. A.
Fraietta
,
J. L.
Hope
,
A. J.
Carey
,
Y. M.
Mueller
,
O. U.
Kawalekar
,
A. J.
Fike
,
C. H.
June
,
P. D.
Katsikis
.
2016
.
Phosphatidylinositol 3-Kinase p110δ isoform regulates CD8+ T cell responses during acute viral and intracellular bacterial infections.
J. Immunol.
196
:
1186
1198
.
129
Rolf
,
J.
,
S. E.
Bell
,
D.
Kovesdi
,
M. L.
Janas
,
D. R.
Soond
,
L. M. C.
Webb
,
S.
Santinelli
,
T.
Saunders
,
B.
Hebeis
,
N.
Killeen
, et al
.
2010
.
Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction.
J. Immunol.
185
:
4042
4052
.
130
Liu
,
D.
,
J. E.
Uzonna
.
2010
.
The p110 δ isoform of phosphatidylinositol 3-kinase controls the quality of secondary anti-Leishmania immunity by regulating expansion and effector function of memory T cell subsets.
J. Immunol.
184
:
3098
3105
.
131
Bowers
,
J. S.
,
K.
Majchrzak
,
M. H.
Nelson
,
B. A.
Aksoy
,
M. M.
Wyatt
,
A. S.
Smith
,
S. R.
Bailey
,
L. R.
Neal
,
J. E.
Hammerbacher
,
C. M.
Paulos
.
2017
.
PI3Kδ inhibition enhances the antitumor fitness of adoptively transferred CD8 + T cells.
Front. Immunol.
8
:
1221
.
132
Abu Eid
,
R.
,
S.
Ahmad
,
Y.
Lin
,
M.
Webb
,
Z.
Berrong
,
R.
Shrimali
,
T.
Kumai
,
S.
Ananth
,
P. C.
Rodriguez
,
E.
Celis
, et al
.
2017
.
Enhanced therapeutic efficacy and memory of tumor-specific CD8 T cells by ex vivo PI3K-δ inhibition.
Cancer Res.
77
:
4135
4145
.
133
Rafii
,
S.
,
D.
Roda
,
E.
Geuna
,
B.
Jimenez
,
K.
Rihawi
,
M.
Capelan
,
T. A.
Yap
,
L. R.
Molife
,
S. B.
Kaye
,
J. S.
de Bono
,
U.
Banerji
.
2015
.
Higher risk of infections with PI3K-AKT-mTOR pathway inhibitors in patients with advanced solid tumors on phase I clinical trials.
Clin. Cancer Res.
21
:
1869
1876
.

The authors have no financial conflicts of interest.