Cytokine-mediated intracellular signaling pathways are fundamental for the development, activation, and differentiation of lymphocytes. These distinct processes underlie protection against infectious diseases after natural infection with pathogens or immunization, thereby providing the host with long-lived immunological memory. In contrast, aberrant cytokine signaling can also result in conditions of immune dysregulation, such as early-onset autoimmunity. Thus, balanced signals provided by distinct cytokines, and delivered to specific cell subsets, are critical for immune homeostasis. The essential roles of cytokines in human immunity have been elegantly and repeatedly revealed by the discovery of individuals with mutations in cytokine ligands, receptors, and downstream transcription factors that cause primary immunodeficiency or autoimmune conditions. In this article, we review how the discovery and characterization of such individuals has identified nonredundant, and often highly specialized, functions of specific cytokines and immune cell subsets in human lymphocyte biology, host defense against infections, and immune regulation.

The generation of lymphocytes from stem cell precursors in bone marrow, thymus, and fetal tissues, and their subsequent differentiation into effector cells, requires signals provided by a myriad of surface receptors, including clonotypic T and B cell Ag receptors and those belonging to Ig and TNFR superfamilies, chemokine receptors and cytokine receptors. The biological effects of many cytokines are mediated by JAK/STAT signaling pathways (13). Four JAKs (JAK1, JAK2, JAK3, and Tyk2) and seven STATs (STAT1, 2, 3, 4, 5a, 5b, and 6) have been identified in mammalian genomes (1, 2). JAKs associate with the cytoplasmic domains of cytokine receptors and, after engagement by specific ligands, phosphorylate key tyrosine residues to provide docking sites for STATs. Receptor-associated STATs undergo JAK-mediated phosphorylation, resulting in the formation of multimers that translocate to the nucleus and bind specific DNA sequences, thereby regulating expression of target genes (13).

Approximately 60 different cytokines have been identified; these include ILs (IL-1 through IL-38), IFNs, TGFs, and members of the TNF superfamily (4). Most cytokines have pleiotropic effects on different immune cells; there is also substantial overlap in their function. Furthermore, ILs and IFNs can activate numerous JAKs and STATs (5). In vivo mouse models and in vitro analyses have identified the key biology of cytokines and informed us that cytokines are critical for lymphocyte development and differentiation. However, the nonredundant functions of specific cytokines in the setting of natural infection and immune dysregulation in humans are constantly being elegantly revealed by the discovery and characterization of individuals with monogenic mutations in cytokine signaling pathways that manifest as immunodeficient and/or autoimmune states (3, 68). Currently, loss-of-expression or loss-of-function (LOF) mutations have been identified in genes encoding cytokines (IL10, IL17F, IL12B, IL21), cytokine receptors (IL2RA, IL2RG, IL7RA, IL10RA, IL10RB, IL11RA, IL12RB1, IL17RA, IL7RC, IL21R, IFNGR1, IFNGR2, IFNAR2), JAKs (JAK1, JAK3, TYK2), transcription factors activated by specific cytokines (STAT1, STAT2, STAT3, STAT5B), and transcription factors that regulate lymphocyte fate (FOXP3, RORC), resulting in impaired development or effector function of different immune cells (Table I) (68). Remarkably, activating or gain-of-function (GOF) mutations have also been identified in some of these genes—JAK1 (9), STAT1 (10, 11), STAT3 (1214), and STAT5B (15) (Table I)—indicating that dysregulated activity of key transcription factors can also be deleterious to immune cell function, and thus human health. In this review, we provide an overview of how the study of rare “experiments of nature” has delineated fundamental and unique functions of cytokines, and the requirements for their associated signaling pathways, in human lymphocyte biology, and how these findings reveal mechanisms of disease pathogenesis and are impacting the diagnosis, management, and treatment of individuals with monogenic immunological dyscrasias.

Table I.
Gene mutations in cytokine signaling pathways affecting human lymphocyte development or function
Mutated GeneMechanism of DiseaseClinical Phenotype and Cellular Defects
IL2RG X-linked LOF B+TNK SCID 
JAK3 AR LOF Impaired B cell responses caused by lack of T cell help 
  Persistent B cell defect (poor responses in vivo, ↓ memory B cells) post-HSCT in nonconditioned patients due to intrinsic requirement of γc cytokine signaling 
  No ILCs 
IL7RA AR LOF B+TNK+ combined immunodeficiency 
STAT3 AD LOF Staphylococcus aureus, Streptococcus pneumonia, Candida albicans infections (CMC) 
  Eczema, vascular/musculoskeletal/dental/connective tissue defects 
  Impaired humoral immunity, but hyper-IgE 
  B cell lymphoma 
  ↓ Th17, Tfh memory CD4+ T cells; ↓ Th17 and Tfh cells from naive CD4+ T cells in vitro 
  ↑ Th2 cytokines 
  ↓ Memory B cells, ↓ naive B cell differentiation into plasmablasts in vitro 
  ↓ MAIT cells, ↓ iNKT cells 
IL21/IL21R AR LOF Combined immunodeficiency 
  Disseminated cryptosporidium infection, susceptibility to Pneumocystis jiroveci and fungal infections 
  Impaired humoral immunity, increased serum IgE 
  ↓ Th17 and Tfh memory CD4+ T cells; ↓ Th17 and Tfh cells from naive CD4+ T cells in vitro 
  ↑ Th2 cytokines 
  ↓ Total memory and class-switched memory B cells, ↓ naive B cell differentiation into plasmablasts in vitro in response to IL-21 
  ↓ iNKT cells 
TYK2 AR LOF MSMD 
  Some patients susceptible to Salmonella, Brucella, Staphylococcus, herpes viruses; CMC in one 
  ↓ Th1 and Th17 memory CD4+ T cells ex vivo; ↓ generation of Th1 and Th17 cells from naive CD4+ T cells in vitro 
  ↑ Th2 cytokines 
STAT1 AR complete LOF MSMD 
  Infection with herpes viruses (often fatal) 
  ↓ Th1 memory CD4+ T cells; ↓ generation of Th1 cells from naive CD4+ T cells in vitro 
 AD or AR partial LOF MSMD (disseminated BCG and NTM infections) 
  ↓ Th1 memory CD4+ T cells; ↓ generation of Th1 cells from naive CD4+ T cells in vitro 
IL12B; IL12RB1 AR LOF MSMD 
  Candida and Salmonella infection, recurrent leishmaniasis in some patients 
  ↓ Th1 and Th17 memory CD4+ T cells ex vivo; ↓ generation of Th1 and Th17 cells from naive CD4+ T cells in vitro 
  ↓ Generation of Tfh cells from naive CD4+ T cells in vitro; but normal cTfh frequencies ex vivo (indicating compensatory pathways for Tfh generation in vivo) 
  ↑ Th2 cytokines 
  ↓ MAIT cells 
  ↓ IFN-γ production by ILC1 cells 
IFNGR1; IFNGR2 AR or AD MSMD 
  ↓ Generation of Th1 cells from naive CD4+ T cells in vitro (unable to respond to autocrine/paracrine IFN-γ) 
  ↑ Th2 cytokines 
RORC AR LOF MSMD, CMC 
  ↓ Th17 memory CD4+ T cells ex vivo; ↓ Th17 cells from naive CD4+ T cells in vitro 
  ↑ Th2 cytokines 
  ↓ MAIT cells, ↓ iNKT cells; ↓ ILC3 cells 
STAT1 AD GOF CMC 
  Infection with other pathogens including herpes viruses, dimorphic yeast, mycobacteria 
  Autoimmune manifestations 
  Impaired humoral immunity 
  ↓ Th17 memory CD4+ T cells; ↓ generation of Th17 and Tfh cells from naive CD4+ T cells in vitro 
  ↓ Memory B cells, ↓ B cell differentiation into Ig-secreting cells in vitro 
IL17F; IL17RA; IL17RC; TRAF3IP2 AD (IL-17F); AR (IL17RA; IL17RC; TRAF3IP2) CMC 
  Deficiency of IL-17F homodimers and heterodimers (with IL-17A) 
  Deficiency of IL-17RA or IL-17RC expression or function 
  Deficiency of ACT1, ↓ signaling through IL-17Rs 
  ↓ Responses to Th17 cytokines IL-17A, IL-17F 
STAT3 AD GOF Multiorgan autoimmunity (IPEX-like) 
  Hypogammaglobulinemia, recurrent infections (fungi, mycobacteria) 
  ↓ Treg numbers and/or function 
  ↓ pSTAT5 in response to IL-2 (mimicking CD25/STAT5 deficiency) 
FOXP3 X-linked LOF IPEX; severe immune dysregulation 
  Eczema, allergy, hyper-IgE; hypergammaglobulinemia 
  ↓ Treg numbers or function 
CD25 AR LOF IPEX-like disease; severe immune dysregulation 
  Chronic herpes virus infection, susceptibility to bacterial and fungal infections 
  Normal Treg numbers but likely ↓ Treg function 
  ↓ FOXP3 expression 
STAT5B AR LOF Growth hormone insensitivity 
  IPEX-like disease; severe immune dysregulation 
  Chronic herpes virus and bacterial infections 
  ↓ Tregs 
  Possibly ↑ Th17, Th2, Tfh cells 
IL10; IL10RA; IL10RB AR LOF Early-onset fistulizing inflammatory bowel disease 
  Impaired IL-10–mediated immune regulation 
  ↑ Th2, Th17 cytokines 
Mutated GeneMechanism of DiseaseClinical Phenotype and Cellular Defects
IL2RG X-linked LOF B+TNK SCID 
JAK3 AR LOF Impaired B cell responses caused by lack of T cell help 
  Persistent B cell defect (poor responses in vivo, ↓ memory B cells) post-HSCT in nonconditioned patients due to intrinsic requirement of γc cytokine signaling 
  No ILCs 
IL7RA AR LOF B+TNK+ combined immunodeficiency 
STAT3 AD LOF Staphylococcus aureus, Streptococcus pneumonia, Candida albicans infections (CMC) 
  Eczema, vascular/musculoskeletal/dental/connective tissue defects 
  Impaired humoral immunity, but hyper-IgE 
  B cell lymphoma 
  ↓ Th17, Tfh memory CD4+ T cells; ↓ Th17 and Tfh cells from naive CD4+ T cells in vitro 
  ↑ Th2 cytokines 
  ↓ Memory B cells, ↓ naive B cell differentiation into plasmablasts in vitro 
  ↓ MAIT cells, ↓ iNKT cells 
IL21/IL21R AR LOF Combined immunodeficiency 
  Disseminated cryptosporidium infection, susceptibility to Pneumocystis jiroveci and fungal infections 
  Impaired humoral immunity, increased serum IgE 
  ↓ Th17 and Tfh memory CD4+ T cells; ↓ Th17 and Tfh cells from naive CD4+ T cells in vitro 
  ↑ Th2 cytokines 
  ↓ Total memory and class-switched memory B cells, ↓ naive B cell differentiation into plasmablasts in vitro in response to IL-21 
  ↓ iNKT cells 
TYK2 AR LOF MSMD 
  Some patients susceptible to Salmonella, Brucella, Staphylococcus, herpes viruses; CMC in one 
  ↓ Th1 and Th17 memory CD4+ T cells ex vivo; ↓ generation of Th1 and Th17 cells from naive CD4+ T cells in vitro 
  ↑ Th2 cytokines 
STAT1 AR complete LOF MSMD 
  Infection with herpes viruses (often fatal) 
  ↓ Th1 memory CD4+ T cells; ↓ generation of Th1 cells from naive CD4+ T cells in vitro 
 AD or AR partial LOF MSMD (disseminated BCG and NTM infections) 
  ↓ Th1 memory CD4+ T cells; ↓ generation of Th1 cells from naive CD4+ T cells in vitro 
IL12B; IL12RB1 AR LOF MSMD 
  Candida and Salmonella infection, recurrent leishmaniasis in some patients 
  ↓ Th1 and Th17 memory CD4+ T cells ex vivo; ↓ generation of Th1 and Th17 cells from naive CD4+ T cells in vitro 
  ↓ Generation of Tfh cells from naive CD4+ T cells in vitro; but normal cTfh frequencies ex vivo (indicating compensatory pathways for Tfh generation in vivo) 
  ↑ Th2 cytokines 
  ↓ MAIT cells 
  ↓ IFN-γ production by ILC1 cells 
IFNGR1; IFNGR2 AR or AD MSMD 
  ↓ Generation of Th1 cells from naive CD4+ T cells in vitro (unable to respond to autocrine/paracrine IFN-γ) 
  ↑ Th2 cytokines 
RORC AR LOF MSMD, CMC 
  ↓ Th17 memory CD4+ T cells ex vivo; ↓ Th17 cells from naive CD4+ T cells in vitro 
  ↑ Th2 cytokines 
  ↓ MAIT cells, ↓ iNKT cells; ↓ ILC3 cells 
STAT1 AD GOF CMC 
  Infection with other pathogens including herpes viruses, dimorphic yeast, mycobacteria 
  Autoimmune manifestations 
  Impaired humoral immunity 
  ↓ Th17 memory CD4+ T cells; ↓ generation of Th17 and Tfh cells from naive CD4+ T cells in vitro 
  ↓ Memory B cells, ↓ B cell differentiation into Ig-secreting cells in vitro 
IL17F; IL17RA; IL17RC; TRAF3IP2 AD (IL-17F); AR (IL17RA; IL17RC; TRAF3IP2) CMC 
  Deficiency of IL-17F homodimers and heterodimers (with IL-17A) 
  Deficiency of IL-17RA or IL-17RC expression or function 
  Deficiency of ACT1, ↓ signaling through IL-17Rs 
  ↓ Responses to Th17 cytokines IL-17A, IL-17F 
STAT3 AD GOF Multiorgan autoimmunity (IPEX-like) 
  Hypogammaglobulinemia, recurrent infections (fungi, mycobacteria) 
  ↓ Treg numbers and/or function 
  ↓ pSTAT5 in response to IL-2 (mimicking CD25/STAT5 deficiency) 
FOXP3 X-linked LOF IPEX; severe immune dysregulation 
  Eczema, allergy, hyper-IgE; hypergammaglobulinemia 
  ↓ Treg numbers or function 
CD25 AR LOF IPEX-like disease; severe immune dysregulation 
  Chronic herpes virus infection, susceptibility to bacterial and fungal infections 
  Normal Treg numbers but likely ↓ Treg function 
  ↓ FOXP3 expression 
STAT5B AR LOF Growth hormone insensitivity 
  IPEX-like disease; severe immune dysregulation 
  Chronic herpes virus and bacterial infections 
  ↓ Tregs 
  Possibly ↑ Th17, Th2, Tfh cells 
IL10; IL10RA; IL10RB AR LOF Early-onset fistulizing inflammatory bowel disease 
  Impaired IL-10–mediated immune regulation 
  ↑ Th2, Th17 cytokines 

For more details, see Refs. 4, 68, 11, 12, 24, 60, 65, 66, 73, 90, and 92.

BCG, Bacillus Calmette–Guérin; CMC, chronic mucocutaneous candidiasis; cTfh, circulating Tfh; HSCT, hematopoietic stem cell transplant; ILC, innate lymphoid cell; iNKT, invariant NKT; IPEX, immune dysregulation, polyendocrinopathy, and enteropathy, X-linked; MAIT, mucosal-associated invariant T; MSMD, Mendelian susceptibility to mycobacterial disease; NTM, nontuberculous mycobacterial; Tfh, T follicular helper; Treg, regulatory T cell.

A seminal discovery in immunology was the finding that the γ-chain (γc) of the IL-2R was also a component of receptor complexes for IL-4 and IL-7 (1619). With the discovery of additional cytokines, IL-2Rγc was found to also be a component of the receptors for IL-9 (20), IL-15 (21), and IL-21 (22). Mutations in IL2RG encoding γc cause X-linked SCID (X-SCID) (23), which is characterized by extreme susceptibility to infection with almost all pathogens (24). The cellular basis for X-SCID is the absence of T cells and NK cells. Remarkably, B cells develop in X-SCID, but because of the lack of T cells they are functionally impaired (24) (Table I). An autosomal recessive (AR) form of TNKB+ SCID that clinically phenocopies X-SCID/IL2RG deficiency is caused by mutations in JAK3 (25, 26) (Table I). This finding established that γc-associated cytokines predominantly required JAK3 for intracellular signaling. Importantly, the subsequent identification of individuals with mutations in IL7R presenting with TNK+B+ SCID definitively demonstrated that disrupted signaling through IL-7R underlies the T cell deficiency in IL2RG/JAK3 SCID but was redundant for NK cell development (27) (Table I). Although no individuals have been found with inactivating mutations in IL15R, the inability of NK cells to develop in IL2RG/JAK3 SCID is likely due to impaired signaling through the IL-15R/γc complex.

After their development, immune responses require lymphocytes to differentiate into effector cells. Studies of human primary immunodeficiencies (PIDs) have revealed critical requirements for cytokines and JAK/STAT signaling in the generation of specialized subsets of effector T cells and B cells.

B cells.

B cells develop from hematopoietic precursor cells in bone marrow and fetal liver (28). The key function of B cells is to produce Abs against foreign pathogens or their secreted products (28). B cells maintain long-lived humoral immunity by differentiating into memory and Ab-secreting plasma cells after exposure to pathogens or vaccines (29, 30). This occurs in germinal centers (GCs) in secondary lymphoid tissues and is dependent on signals provided by cognate CD4+ T cells. Indeed, the molecular and cellular characterization of CD40L, predominantly expressed by CD4+ T cells and belonging to the TNF superfamily of cytokines (31), and the prompt identification of individuals with LOF mutations in CD40LG and CD40 (reviewed in Ref. 32) defined the central role of CD40L/CD40 interactions in establishing GCs.

Although human B cell development is independent of γc cytokines (24), differentiation of B cells into memory and plasma cells requires cytokines provided by CD4+ T cells (33, 34). IL-21 is a potent growth and differentiation factor for human B cells, inducing impressive proliferation, class switching, and production of large amounts of all Ig isotypes by naive, memory, and GC B cells (33, 35, 36) (Fig. 1). This is due to IL-21 inducing the molecular machinery required for isotype switching (AICDA, encoding activation-induced cytidine deaminase) and plasma cell differentiation (PRDM1 [Blimp-1], XBP1; Fig. 1) (33, 34, 37). The receptor for IL-21 comprises IL-21R and γc (22). Binding of IL-21 to the IL-21R activates JAK1 and JAK3, with subsequent phosphorylation of STAT1, STAT3, and STAT5 (5, 22, 37). Remarkably, pathogenic mutations have been identified at each stage of IL-21 signaling, and studies of these affected individuals have revealed a key role for IL-21 in human B cell differentiation in vivo.

FIGURE 1.

Cytokine-induced differentiation of human B cells: requirement for IL-21/IL-21R/γc/JAK3/STAT3 signaling in vitro and in vivo. (A) In response to in vitro stimulation with IL-21, human naive B cells undergo intense proliferation, Ig class switching, predominantly to IgG1, IgG3, and IgA1, or differentiation into plasmablasts secreting all major Ig isotypes. These differentiation events coincide with the induction of AICDA (required for class switching) and BLIMP-1/XBP-1 (required for plasma cell formation). The ability of IL-21 to induce naive B cells to differentiate into plasmablasts/plasma cells in vitro was compromised by LOF mutations in STAT3, GOF mutations in STAT1, or null mutations in IL21R, IL2RG, or JAK3. Remarkably, AICDA induction and Ig class switching were not affected by STAT3 LOF mutations. (B) Naive B cells differentiate into memory cells in response to signals provided by Ag, Tfh cells, and dendritic cells. Memory B cell generation is compromised by LOF mutations in STAT3, IL21, IL21R, IL2RG, or JAK3, or GOF mutations in STAT1.

FIGURE 1.

Cytokine-induced differentiation of human B cells: requirement for IL-21/IL-21R/γc/JAK3/STAT3 signaling in vitro and in vivo. (A) In response to in vitro stimulation with IL-21, human naive B cells undergo intense proliferation, Ig class switching, predominantly to IgG1, IgG3, and IgA1, or differentiation into plasmablasts secreting all major Ig isotypes. These differentiation events coincide with the induction of AICDA (required for class switching) and BLIMP-1/XBP-1 (required for plasma cell formation). The ability of IL-21 to induce naive B cells to differentiate into plasmablasts/plasma cells in vitro was compromised by LOF mutations in STAT3, GOF mutations in STAT1, or null mutations in IL21R, IL2RG, or JAK3. Remarkably, AICDA induction and Ig class switching were not affected by STAT3 LOF mutations. (B) Naive B cells differentiate into memory cells in response to signals provided by Ag, Tfh cells, and dendritic cells. Memory B cell generation is compromised by LOF mutations in STAT3, IL21, IL21R, IL2RG, or JAK3, or GOF mutations in STAT1.

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Dominant negative LOF mutations in STAT3 cause the multisystemic disorder autosomal dominant (AD) hyper-IgE syndrome (38, 39). In addition to susceptibility to infections with Staphylococcus and Candida, these patients have defects in Ag-specific Ab responses (8, 40, 41). Consistent with this, there are marked reductions in memory B cells in these patients, and their naive B cells are unable to differentiate into plasmablasts in vitro in response to IL-21 (42, 43) (Fig. 1, Table I). These findings suggested that IL-21R/STAT3 signaling was important for generating memory B cells and Ag-specific Abs.

At the time of this study, this conclusion was hypothetical because numerous cytokines in addition to IL-21, such as IL-6 and IL-10, can also activate STAT3 and promote human B cell differentiation (4, 34). However, these predictions were confirmed by several subsequent investigations. B cell differentiation was examined in patients with IL2RG or JAK3 mutations who had undergone hematopoietic stem cell transplantation. In general, in the absence of pretransplant conditioning, T cells are donor-derived, whereas B cells remain of host origin. Thus, these patients are chimeric, with normal T cells, but γc-deficient B cells. In contrast, in patients who receive pretransplant myeloablative conditioning, both B cells and T cells are derived from the healthy donor (44, 45). It was found that, reminiscent of individuals with STAT3 LOF mutations, the proportions of memory B cells remained significantly reduced in patients with γc-deficient B cells, despite the availability of cytokines provided by cognate CD4+ T cells (44, 45) (Fig. 1). These findings narrowed the candidates of STAT3-activating cytokines to those that use γc. Because B cells develop in the absence of IL-7R (27), IL-2, IL-9, and IL-15 have modest (IL-2, IL-15), if any (IL-9), effect on human B cell differentiation in vitro (34); mutations in CD25 (IL2RA) result in normal or elevated levels of serum Ig (4649); and IL-4 can signal through an alternative receptor that does not require γc (i.e., IL-13R) (4, 50), IL-21 was the only plausible cytokine capable of regulating human memory B cell generation in vivo in a γc/STAT3-dependent manner (44). This was indeed confirmed with the subsequent descriptions of patients with LOF mutations in IL21R (5153) and IL21 (54). These individuals have hypogammaglobulinemia, poor humoral responses after natural infection or vaccination, reduced frequencies of memory B cells, and a paucity of class-switched memory B cells. Thus, signaling via the IL-21/IL-21R/γc/JAK3/STAT3 pathway is fundamental for generating effective humoral immune responses in humans (Fig. 1, Table I). Even though IL-21 has diverse functions on many types of immune cells (37), studies of transplanted IL2RG/JAK3 SCID patients infer a B cell–intrinsic requirement for IL-21R/STAT3 signaling in this process (44, 45). Indeed, studies of mice lacking IL-21R or STAT3 only in B cells established the B cell–intrinsic nature of IL-21R/STAT3 signaling in regulating the survival, GC formation, Ig secretion, and selection of high-affinity B cells in response to T-dependent Ags (55, 56). Interestingly, STAT1 GOF mutations result in a comparable B cell defect as STAT3 LOF mutations, because these individuals have impaired humoral immune responses (11), they lack memory B cells, and their naive B cells exhibit defective in vitro differentiation to Ig-secreting cells (57, 58) (Fig. 1, Table I).

Analyses of PIDs have also revealed redundant or compensatory pathways in human B cell function in vivo, despite in vitro studies predicting otherwise. First, although IL-10 can promote human B cell differentiation in vitro (4, 34), individuals with mutations in IL10, IL10RA (encoding IL-10R1), or IL10RB (encoding IL-10R2) have elevated serum Ig levels and normal levels of Ag-specific Ab (59). Second, although IL-21 can activate multiple JAKs and STATs (5, 22, 37), STAT1 LOF, JAK1 LOF, or JAK1 GOF mutations have no effect on humoral immunity (9, 42, 43, 60, 61). Third, signaling through the IL-13R [comprising IL-4R/IL-13Rα1 (4, 50)] by either IL-4 or IL-13 was unable to compensate for an inability to signal through γc (44), despite the well-established findings that these cytokines induce proliferation and Ig class switching in human B cells in vitro (4, 34). These findings further underscore the central role of IL-21/IL-21R/γc/JAK3/STAT3 signaling in regulating human B cell responses in vivo (Fig. 1) and reveal this pathway to be a key target for therapeutic manipulation of humoral immunity in the settings of vaccination, autoimmunity, or immunodeficiency.

CD4+ T cells.

CD4+ T cells play critical and nonredundant roles in mediating immune responses against foreign pathogens. This is due to the ability of naive CD4+ T cells to differentiate into distinct populations with specialized effector functions. As such, Th1, Th2, and Th17 cells have been implicated in antiviral, antiparasitic, and antifungal immunity, respectively, whereas T follicular helper (Tfh) cells control humoral immunity by regulating B cell differentiation. Regulatory T cells (Tregs) maintain immune homeostasis and restrain immune responses to avoid immune-mediated pathology (62, 63). The study of monogenic PIDs has provided invaluable insights into the requirements for human CD4+ T cell differentiation and function.

Th1 cells.

Induction of Th1 cells is primarily driven by IL-12, which activates STAT4 to upregulate T-BET and subsequently induces IFN-γ production. IFN-γ can promote its own production by signaling through the IFN-γR and activating STAT1 (8, 62, 63) (Fig. 2A). The importance of Th1 cells to host defense is revealed by patients with inborn errors that compromise production or function of IFN-γ. Such individuals present with Mendelian susceptibility to mycobacterial disease (MSMD), characterized clinically by infection with weakly virulent strains of mycobacteria, such as the Bacillus Calmette–Guérin vaccine and nontuberculosis mycobacteria (60). Thus, mutations in IL12B (encoding IL-12p40), IL12RB1, or TYK2, functioning downstream of the IL-12R, impair the development of IFN-γ–producing Th1 cells (57, 58, 6467) (Fig. 2A). Although the initial events of IL-12R signaling are unaffected by LOF mutations in IFNGR1/2 or STAT1, these mutations also impaired IL‐12–mediated IFN-γ production by CD4+ T cells (57, 58), underscoring the importance of IFN-γ in enhancing its own production (Fig. 2A). Collectively, these data revealed IL-12/IL-12R/TYK2 signaling in human CD4+ T cells induces IFN-γ, which is subsequently maintained by an autocrine feed-forward loop involving IFN-γ/IFN-γR/STAT1 (Fig. 2A, Table I).

FIGURE 2.

Cytokine signaling pathways required to generate effector CD4+ T cells. Illustrated are the pathways involving cytokines, cytokine receptors, JAKs, STATs, and downstream transcription factors that underpin the differentiation of naive CD4+ T cells into (A) Th1, (B) Th17, (C) Tfh, and (D) Tregs. The molecules shown in red text have been found to be mutated in specific human PIDs and impair either the generation or effector function of the relevant CD4+ T cell subset. For Tfh and Th17 cells, the red arrows indicate pathways that repress effector CD4+ T cell generation; mutations in these pathways result in exacerbated Tfh and Th17 function. Although not discussed in this review, dominant mutations in CTLA4 have been identified in individuals with autoimmunity and have been found to impair the Treg function (6).

FIGURE 2.

Cytokine signaling pathways required to generate effector CD4+ T cells. Illustrated are the pathways involving cytokines, cytokine receptors, JAKs, STATs, and downstream transcription factors that underpin the differentiation of naive CD4+ T cells into (A) Th1, (B) Th17, (C) Tfh, and (D) Tregs. The molecules shown in red text have been found to be mutated in specific human PIDs and impair either the generation or effector function of the relevant CD4+ T cell subset. For Tfh and Th17 cells, the red arrows indicate pathways that repress effector CD4+ T cell generation; mutations in these pathways result in exacerbated Tfh and Th17 function. Although not discussed in this review, dominant mutations in CTLA4 have been identified in individuals with autoimmunity and have been found to impair the Treg function (6).

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Th2 cells.

Th2 cells produce IL-4, IL-5, and IL-13 and have important roles not only in extracellular immune responses but also in the pathogenesis of allergic, asthmatic, and atopic diseases (4, 8, 62). No gene defects have yet been identified that abolish Th2 immunity (6). However, analysis of CD4+ T cells from PID patients has revealed several pathways that are involved in restraining Th2 responses. Thus, memory CD4+ T cells from patients with LOF mutations in IL12RB1, IFNGR1, TYK2, STAT3, RORC, IL21/IL21R, or IL10RA have enhanced production of Th2 cytokines (57, 58, 64) (Table I), demonstrating the counterregulation of Th2 cells by Th1 or Th17 cells and the immunoregulatory function of IL-10.

Some of these patient groups—STAT3 LOF and some TYK2 or IFNGR1 LOF—have elevated IgE levels and features of atopy (8, 38, 39, 64, 68, 69), consistent with heightened Th2 responses in some of these settings. However, it is striking that despite the clearly dysregulated production of Th2 cytokines at the cellular level, this is insufficient to trigger diseases often associated with exacerbated Th2 immunity in most individuals with impaired IFN-γ–mediated immunity (60, 65, 66, 68, 70, 71). Thus, because skewing toward Th2 cytokine in individuals with defects in IFN-γ–mediated immunity is largely subclinical, additional defects must contribute to the development of severe Th2-driven immunopathologies.

Th17 cells.

Th17 cells have been implicated in numerous autoimmune conditions, such as inflammatory bowel disease, psoriasis, and ankylosing spondylitis (4, 72). However, Th17 cells are also important for host defense at mucocutaneous surfaces, particularly against fungal and staphylococcal infections (73). Human Th17 cells can be generated from naive precursors in vitro in the presence of TGF-β, IL-1β, IL-6, IL-21, and IL-23 (8, 62, 63, 72). These factors activate STAT3 and induce RORγt, which regulates production of the cytokines IL-17A, IL-17F, and IL-22, as well as several additional features of Th17 cells, including CCR6 and CCL20 (Fig. 2B).

Individuals with mutations that compromise IL‐17–mediated immunity develop chronic mucocutaneous candidiasis (CMC) and have provided invaluable insights into the cytokine pathways that regulate Th17 cell differentiation and function (73). LOF mutations in STAT3 and RORC abolish Th17 cell generation in vitro and in vivo (57, 58, 71, 7476) (Fig. 2B). These findings revealed the essential roles of STAT3 and RORγt in Th17 formation and provided a mechanism for the high incidence [∼85% (73)] of CMC in these patients. Interestingly, increased proportions of IL-17–producing CD4+ T cells have been detected in only a minority of individuals with STAT3 GOF mutations (13), suggesting that excessive STAT3 signaling does not skew CD4+ T cell differentiation to a Th17 fate. IL12RB1, IL21/IL21R, or TYK2 LOF mutations dramatically reduced, but did not abolish, Th17 cells (51, 57, 58, 64, 67, 74, 75). Thus, IL-23 (via IL-12Rβ1) and IL-21 appear to be the predominant STAT3-activating cytokines involved in Th17 generation (Fig. 2B) and explain the incidence of CMC in 10–30% of individuals with these pathogenic gene mutations (73) (Table I).

STAT1 GOF mutations also cause CMC in >95% of affected individuals and impede Th17 development (11, 57, 58, 73) (Table I). Although the mechanism underlying defective Th17 generation caused by STAT1 GOF remains incompletely determined, it has been suggested that a stronger cellular response to the STAT1-dependent cytokines IFN-α/β, IFN-γ, and IL-27 inhibits Th17 development (10, 11) (Fig. 2B). Alternatively, STAT1 GOF mutations could suppress STAT3 function (57, 58) (Fig. 2B). In contrast, STAT1 LOF mutations have no effect on Th17 cell development, whereas naive and memory CD4+ T cells from patients with IL‐10R deficiency exhibited markedly increased production of Th17 cytokines (57, 58), demonstrating that IL-10 potently inhibits Th17 responses (Fig. 2B). Consistent with these findings, inflammatory bowel disease caused by IL10RA mutations has successfully been treated with the anti–IL-23 mAb ustekinumab (Dr. R. Abraham, Mayo Clinic, Rochester, MN, personal communication). IL-2/STAT5 signaling constrains murine Th17 development (77). By compromising IL-2 signaling, STAT5B LOF mutations may result in exacerbated Th17 responses (Fig. 2B), thereby contributing to autoimmunity in individuals with STAT5B deficiency (72).

Whereas STAT3, RORC, IL12RB1, IL21R, and TYK2 LOF and STAT1 GOF mutations impact the generation of human Th17 cells, other mutations impair the ability of target cells to respond to the effector cytokines of these cells. Thus, mutations in IL17F (78), IL17RA (78), IL17RC (79), or TRAF3IP2 (encoding ACT1, downstream of IL-17R) (80) compromise IL-17 signaling either by: 1) preventing production of IL-17F homodimers or IL-17A/F heterodimers (78); 2) abolishing expression/function of IL-17RA or IL-17RC (receptors for IL-17A/F) (78, 79); or 3) crippling signaling downstream of IL-17RA/C (80), respectively (Fig. 2B, Table I). Even though IL-22 production is impaired by STAT3 mutations (57, 74), any residual IL-22 would be unable to elicit antimicrobial responses in epithelial cells because IL-22R signals via STAT3 (4, 5). Together, the molecular requirements for the generation and function of human Th17 cells have been elegantly illustrated by analyzing monogenic PIDs. These analyses also highlighted the critical role of Th17 cells in protection against mucocutaneous fungal and staphylococcal infections, and the redundant function of these cells in immune responses against other pathogens.

Tfh cells.

Tfh cells play important roles in humoral immunity by supporting differentiation of B cells into memory and plasma cells. Tfh cells are characterized by high expression of CXCR5, BCL-6, CD40L, ICOS, and PD-1, and the cytokines IL-4, IL-10, and IL-21 (33, 81). Studies in mice have revealed important roles for IL-6, IL-12, IL-21, IL-27, STAT1, and STAT3 in the generation and function of Tfh cells. Conversely, IL-2/STAT5 signaling restrains murine Tfh cells (reviewed in Ref. 33, 81). Analysis of Tfh cells in human diseases has been challenging because of limited access to lymphoid tissues, where Tfh cells are predominantly located. However, the finding that peripheral blood CXCR5+CD4+ memory T cell subsets are the circulating counterparts of lymphoid tissue Tfh cells has facilitated such investigations (33, 81).

Assessing PIDs has revealed cytokines and associated signaling pathways required for the differentiation and function of human circulating Tfh (cTfh) cells, and by inference bona fide Tfh cells localized in lymphoid tissues. Thus, proportions of B cell helper cTfh cells were reduced in patients with LOF mutations in IL10R, IL21, IL21R, and STAT3, and GOF mutations in STAT1 (57, 82, 83) or STAT5B (15), respectively, with GOF mutations in STAT5B likely mimicking persistent signaling via IL-2 to suppress Tfh cell formation (Fig. 2C, Table I).

Naive CD4+ T cells differentiate into Tfh-like cells in vitro, defined by expression of IL-21, CXCR5, and ICOS and the ability to promote B cell differentiation, after stimulation with IL-12. Importantly, the ability to generate Tfh-like cells in vitro was also compromised by STAT3 or IL21R LOF or STAT1 GOF mutations (58, 82). These findings revealed a key role for autocrine IL-21/STAT3 signaling in generating human Tfh cells. Because the effect of STAT1 GOF phenocopied that of STAT3 LOF, hyperactive STAT1 appears to have an inhibitory effect on STAT3-mediated CD4+ T cell differentiation (Fig. 2C, Table I). The findings of impaired cTfh cell generation or function in these PIDs is consistent with impaired Ag-specific Ab responses in individuals with IL21/IL21R LOF (5154), STAT3 LOF (4042), or STAT1 GOF (11) mutations.

Not surprisingly, LOF mutations in IL12RB1 or TYK2 abolished or reduced Tfh cell generation in vitro (58, 82, 84). In contrast, these mutations had only a mild effect on the proportions of cTfh cells detected in affected individuals (57, 82, 84). This correlates with intact, and even enhanced, humoral immune responses in individuals with IL12B, IL12RB1, or TYK2 mutations (57, 6466, 69, 84) and suggests that compensatory mechanisms ensure Tfh cell development in the absence of IL-12/IL-12R/TYK2 signaling. This likely occurs via STAT3 downstream of IL-6, IL-21, IL-23, and IL-27 (58, 82, 85) (Fig. 2C, Table I).

Tregs.

Tregs suppress immune responses and maintain self-tolerance (86). The master regulator of Tregs is FOXP3. This was established by identifying patients with mutations in FOXP3 who present with immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX), a devastating early-onset multiorgan autoimmune and lymphoproliferative disease (8790). Subsequent studies established that FOXP3 mutations compromise Treg development and/or function (46, 90) (Fig. 2D, Table I). Tregs express CD25 (IL-2Rα), and IL-2/STAT5 signaling is important for their survival and persistence (86). Furthermore, IL-2/STAT5 can induce or maintain FOXP3 expression in human CD4+ T cells, including Tregs (91). Consistent with these findings, individuals with LOF mutations in CD25/IL2RA (4749) or STAT5B (92) display an IPEX-like syndrome. STAT5B LOF mutations also impair the generation or function of Tregs (46, 92) (Fig. 2D). In the few CD25-deficient patients examined, Tregs were detected at normal frequencies (48, 49). However, given the dependence of Tregs on IL-2, it is likely that CD25-mutant Tregs also have compromised regulatory function (Fig. 2D, Table I).

More recently, STAT3 GOF mutations were found in individuals with early-onset multiorgan autoimmunity (1214). Most patients have decreased proportions of circulating FOXP3+ Tregs and, when possible to assess, their Tregs had decreased suppressive capabilities (1214) (Fig. 2D, Table I). Interestingly, STAT3 GOF lymphocytes exhibited decreased STAT5 phosphorylation in response to IL-2 (13), inferring that hyperactive STAT3 influences the activation of other STAT pathways. In this case, the Treg defect caused by STAT3 GOF may result from impaired IL-2/STAT5–mediated Treg survival, maintenance, or function, mirroring the defect in individuals with STAT5B LOF mutations (13, 46, 92) (Fig. 2D, Table I).

Innate-like T cells.

Unconventional or innate-like T cells include γδ T, invariant NKT (iNKT), and mucosal-associated invariant T (MAIT) cells. Although a great deal of information has been established regarding the function and phenotype of these innate-like T cells, few studies have addressed how disruptions in cytokine signaling affect these cell types. However, several recent studies have shed light on the contributions of specific cytokines and transcription factors on the development and function of human γδ T, iNKT, and MAIT cells.

STAT3 LOF mutations decreased the numbers of peripheral MAIT and iNKT cells; however, γδ T cells numbers were not affected (9395). Furthermore, in the absence of STAT3 signaling, MAIT and γδ T cells were unable to produce IL-17A or IL-17F (93) (Table I). These observations raised the question of which STAT3 cytokines were responsible for maintaining these unconventional T cells. IL21R deficiency decreased NKT cells, suggesting IL-21/IL-21R/STAT3 signaling regulates NKT cells (93) (Table I). In contrast, patients with IL12RB1 mutations had decreased numbers of MAIT cells. Because IL-23, but not IL-12, activated STAT3 in MAIT cells, IL-23 signaling via IL-12Rβ1/IL-23R/STAT3 is likely required to regulate MAIT cell numbers (93) (Table I). Consistent with this conclusion, patients with autoantibodies against IL-12/IL-23 p40 also had reductions in both the numbers and function of MAIT cells (94).

MAIT and iNKT cells are also absent from RORC-deficient individuals (71) (Table I). However, this is due to RORγt mediating T cell survival during TCR rearrangement, rather than a requirement downstream of specific cytokines. Indeed, MAIT cells from STAT3-deficient patients, although reduced in number, had normal expression of RORγt (93), suggesting pathways distinct from cytokine-driven STAT3 activation upregulate RORγt in these cells.

Although these studies have given some insight into the cytokine pathways that regulate unconventional T cells, further work is required to identify additional signaling pathways that control these cells and how deficiencies in MAIT and/or iNKT cells may contribute to the pathophysiology of different PIDs.

Innate lymphoid cells.

Recently, innate lymphoid cells (ILCs) have been identified as important players in immunity in health and disease. ILCs share morphology and function with lymphocytes, yet lack expression of RAG-dependent Ag receptors (96, 97). ILCs can be divided into ILC1, ILC2, and ILC3 populations, with similarities to Th1, Th2, and Th17 cells, respectively (96, 97). IL2RG/JAK3 SCID patients lack all ILCs (98), most likely because of a dependency on IL-7/IL-7R/γc/JAK3 signaling during development, consistent with their high CD127 (IL-7Rα) expression (96, 97).

Functional similarities between ILCs and effector CD4+ T cells can be explained in part by overlapping requirements for differentiation. Thus, although ILC1 cells developed normally in individuals deficient for IL-12Rβ1, their ability to produce IFN-γ was greatly reduced (99). Similarly, production of IL-17 by ILC3 cells was dependent on RORγt, because precursors from patients with RORC mutations failed to develop into mature IL-17–producing ILCs in vitro (100).

Studies in gene-targeted mice have indisputably provided a solid foundation for identifying cytokines that regulate lymphocyte biology (4). However, mice are not humans. As such, detailed investigations of cytokine signaling events that impact human lymphocytes must also be undertaken. Analysis of PIDs is the ideal model system to delineate molecular requirements for human lymphocyte development, differentiation, and function. These studies not only reveal pathways necessary for these processes, but provide critical insight into the nonredundant functions of specific genes, molecules, and signaling pathways in human immune regulation, whether it be in the setting of natural infection or initiation of autoimmunity. Furthermore, by studying PIDs to unravel human immune cell function, mechanisms of disease pathogenesis are revealed, providing opportunities for targeted therapeutic intervention as novel means of treating some of these conditions. This is evidenced by successfully treating: 1) patients with MSMD caused by impaired IFN-γ–mediated immunity with IFN-γ replacement therapy (60, 65, 66), 2) STAT1 GOF mutations with the JAK inhibitor ruxolitinib (11), 3) STAT3 GOF mutations with tocilizumab (anti–IL-6R) (13), and 4) IL10R mutations with ustekinumab. It is easy to envisage individuals with GOF mutations in STAT3 (1214) or STAT5B (15) also being treated with ruxolitinib. PIDs also provide the platform to molecularly characterize additional specialized subsets of lymphocytes, such as Th9, Th22, T follicular regulatory cells, and regulatory B cells, and to understand the unique and redundant functions of these cells in human immunity. Thus, although the absolute numbers of individuals with monogenic conditions of immune dysregulation are low, the contributions these individuals have made to our understanding of human immunology and immune dysregulation are profound. The discovery of mutations in novel genes underlying distinct immunopathologies is occurring at a rapid rate (6). Thus, ongoing analysis of newly identified affected individuals will continue to facilitate exciting breakthroughs in basic, clinical, and applied immunology for many years to come.

We thank our many clinical colleagues and collaborators, as well as the many patients and families, who have made it possible for our laboratories to pursue many of the questions discussed in this review. We are particularly indebted to Jean-Laurent Casanova, Satoshi Okada, Peter Arkwright, Kaan Boztug, Melanie Wong, Paul Gray, Steve Holland, and Gulbu Uzel for ongoing support and input into these projects.

This work was supported by research grants and fellowships awarded by the National Health and Medical Research Council of Australia, the Office of Health and Medical Research of the New South Wales State Government, and the Jeffrey Modell Foundation (to the laboratories of S.G.T., C.S.M., and E.K.D.) and by an Australian Postgraduate Award from the University of New South Wales, Australia (to S.J.P.).

Abbreviations used in this article:

AD

autosomal dominant

AR

autosomal recessive

γc

γ-chain

CMC

chronic mucocutaneous candidiasis

cTfh

circulating Tfh

GC

germinal center

GOF

gain-of-function

ILC

innate lymphoid cell

iNKT

invariant NKT

IPEX

immune dysregulation, polyendocrinopathy, and enteropathy, X-linked

LOF

loss-of-function

MAIT

mucosal-associated invariant T

MSMD

Mendelian susceptibility to mycobacterial disease

PID

primary immunodeficiency

Tfh

T follicular helper

Treg

regulatory T cell

X-SCID

X-linked SCID.

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The authors have no financial conflicts of interest.