Cell signaling pathways regulate much in the life of a cell: from shuttling cargo through intracellular compartments and onto the cell surface, how it should respond to stress, protecting itself from harm (environmental insults or infections), to ultimately, death by apoptosis. These signaling pathways are important for various aspects of the immune response as well. However, not much is known in terms of the participation of cell signaling pathways in Ag presentation, a necessary first step in the activation of innate and adaptive T cells. In this brief review, I discuss the known signaling molecules (and pathways) that regulate how Ags are presented to T cells and the mechanism(s), if identified. Studies in this area have important implications in vaccine development and new treatment paradigms against infectious diseases, autoimmunity, and cancer.

What allows cells to respond to stimuli in specific ways? A priori, one can envisage a stimulus and a cellular response. Unfortunately, in between that stimulus and response is a black box. An external or internal event triggers within a cell a cascade (linear or branched), resulting in the phosphorylation and/or dephosphorylation of specific proteins. As a consequence, these cell signaling pathways have effects upon or within the cell that result in a specific response. For example, the activation of these pathways can stimulate cell migration or arrest. This can be due to the polymerization or depolymerization of cytoskeletal proteins or the rearrangement of proteins or intracellular compartments. Another potential consequence of the activation of these pathways could be activation-induced cell death.

Studies to dissect the specific paths (i.e., proteins that are phosphorylated or dephosphorylated and consequent effects on downstream intracellular proteins) followed by cell signaling pathways have helped us to understand many ways in which cells react to the environment, including infections by pathogens. Because this is a Brief Review, my comments are focused on cell signaling pathways that control the presentation of Ag to conventional and unconventional T cells.

Why would cell signaling pathways even be important for the immune system? Certainly, APCs need to be able to capture and internalize Ag in various forms and by various routes (15). This could be by phagocytosis, pinocytosis, or infection by a pathogen or even taken from within a cell as an endogenous protein or lipid. Ag-loaded molecules need to be able to be transported intracellularly along the cytoskeletal network to their ultimate expression on the cell surface for recognition by T cells. That movement needs direction; this is provided by cell signaling pathways.

APCs primarily use three pathways of Ag presentation; Ags are presented by MHC or MHC-like molecules (15). The first pathway involves MHC class I molecules (2, 618). In the cytosol, endogenously synthesized polypeptide chains are threaded into a barrel-like structure called the proteasome, which contains a variety of proteolytic enzyme activities. As the polypeptide is cleaved, a diverse array of peptides consisting of ∼9–15 aa is generated. These peptides are delivered into the endoplasmic reticulum by the TAP. Upon being loaded onto peptide-receptive MHC class I molecules, endoplasmic reticulum–resident peptidases cleave amino terminal amino acids, resulting in the 8–9-aa peptides that are usually found associated with MHC class I molecules. The peptide-loaded MHC class I molecules are transported through the Golgi to the cell surface, where they are recognized by CD8+ T cells. The second Ag-presentation pathway involves MHC class II molecules (17, 1931). Rather than being synthesized intracellularly within an APC, Ags are taken up by phagocytosis (or pinocytosis) and delivered to late endocytic compartments where they are processed into longer (e.g., 15–20) peptide-sized fragments than those loaded onto MHC class I molecules. Initially, MHC class II molecules are complexed with the invariant chain (Ii). The CLIP portion of the Ii prevents peptide loading until the MHC class II molecules traffic to late endocytic compartments (e.g., MHC class II compartment). It is here that an antigenic peptide replaces the Ii’s CLIP. The newly loaded MHC class II molecule is transported to the cell surface where it is recognized by CD4+ T cells. The third Ag-presentation pathway does not involve peptide Ag presentation. CD1 molecules are MHC class I–like molecules that generally present lipid Ags to invariant, relatively oligoclonal, or even diverse T cells. These lipids can be of microbial origin or from mammalian cells themselves (5, 32). The CD1 family of Ag-presenting molecules consists of two members (based on the human CD1 molecules): group 1 includes CD1a, CD1b, and CD1c molecules, whereas group 2 contains CD1d as its sole member (33). Each of these molecules differs in how they traffic intracellularly and, thereby, how they acquire Ag.

For the sake of completeness, I will note that there are the very interesting MHC class I–like MR1 molecules, which present microbial vitamin B–derived metabolites to a novel T cell subpopulation called mucosal-associated invariant T cells (34, 35). Because so little is known about the cell signaling pathways regulating their function, they are not discussed in this article.

The presentation of specific Ags to T cells by cell–cell interactions results in the production of various cytokines that, in turn, stimulate APCs. For T cells to be stimulated by APCs, cell signaling pathways within the APCs themselves need to be activated; this results in the proper Ags being processed and loaded onto the appropriate Ag-presenting molecule to be expressed on the surface. This is absolutely required for Ag-specific T cells to be activated and perform their effector cell functions.

Which are the most widely studied cell signaling pathways that control classical (i.e., MHC class I and II) and nonclassical (e.g., CD1d) Ag presentation and what are the mechanisms (if known) by which they do this? One of the best understood cell signaling pathway families is that mediated by MAPK (Fig. 1, left panel). Following a cell stimulus, a MAPKKK is phosphorylated which, in turn, phosphorylates a MAPKK. Finally, the MAPKK activates the MAPK, which is transported into the nucleus to mediate its function. The MAPK family consists of three main members: p38, JNK, and ERK (reviewed in Ref. 36). Upon receiving a cell stimulus (e.g., infection with a pathogen or exposure to inflammatory cytokines), the subsequent activation of the MAPK pathways results in inflammation, cell growth, differentiation, or apoptosis. Consequently, the activation of MAPK pathways has the potential to impact the ability of a host’s immune cells to appropriately respond to an infection. Of these three pathways, p38 has been studied the most with regard to Ag processing and presentation.

FIGURE 1.

Activation of the MAPK family of cell signaling molecules. There are three main families of MAPK: p38, ERK and JNK. Each has important roles in the response of a cell to a stimulus. On the left indicates the normal process of events: A cell stimulus results in the activation of a MAP3K (MAPKKK), which in turn phosphorylates a MAP2K (MAPKK). The MAPKK activates the MAPK via phosphorylation which leads to a biological response. The specific biological responses mediated by the individual MAPKs are indicated on the right.

FIGURE 1.

Activation of the MAPK family of cell signaling molecules. There are three main families of MAPK: p38, ERK and JNK. Each has important roles in the response of a cell to a stimulus. On the left indicates the normal process of events: A cell stimulus results in the activation of a MAP3K (MAPKKK), which in turn phosphorylates a MAP2K (MAPKK). The MAPKK activates the MAPK via phosphorylation which leads to a biological response. The specific biological responses mediated by the individual MAPKs are indicated on the right.

Close modal

MAPK p38 can be phosphorylated by two upstream kinases: MKK3 and MKK6 (37). For macrophage (MΦ) maturation (20) and production of IL-12 (38), p38 is required via its stimulation by MKK3 (38). This occurs because MKK3 indirectly activates the IL-12 p40 promoter through its phosphorylation of p38 (39). In MΦs, anisomycin (a p38 activator) enhances LPS-induced IL-12 production; this is blocked by the p38-specific inhibitor SB203580 (39). Blocking p38 also impairs dendritic cell (DC)/T cell clustering, which can, of course, reduce effector T cell activation (39). Interestingly, p38 inhibits (whereas ERK promotes) the differentiation of monocytes into DCs (40). As discussed below, p38 and ERK have similar reciprocal control over CD1d-mediated Ag presentation (4143). Unstimulated DCs have a basal level of p38 that is enhanced following stimulation with anisomycin, a drug that activates p38 and JNK (44). In human (44) and mouse (45) DCs, activation of TLR4 results in the phosphorylation of p38. TLRs have a variety of known effects on APCs; these are discussed later. The other MAPKK that can activate p38, MKK6, increases the APC activity of Langerhans cells by stimulating the NF-κB pathway (46).

MAPK p38 was shown to be important for Ag presentation by classical MHC class I and II molecules. Ag uptake is increased in DCs treated with cyclophin A, which results in p38 activation (47). p38 (and ERK) activation by osteoprotegerin ligand increases costimulatory molecule expression (48), readying APCs for interaction with Ag-specific T cells. In the context of Ag presentation by MHC class I, p38 can help or hinder. For example, p38 phosphorylation following CD40L engagement results in the activation of DCs and expansion of HIV-specific memory CD8+ T cells (49). It was presumed that the expansion of these T cells is MHC class I dependent; however, it was shown recently that SIV peptides can be presented to CD8+ T cells by MHC class II molecules (50). I indicated above that TLR engagement activates p38 in DCs (44, 45); this also results in enhanced Ag presentation by DCs to antitumor T cells via MHC class I molecules (51). In contrast, there is increased Ag uptake for cross-presentation by MHC class I molecules in a Japanese encephalitis virus model when p38 is inhibited (7); thus, p38 appears to be a negative regulator in this model.

p38 activation in DCs (52) and its induction by fragments of the food product gliadin (53) increase costimulatory and MHC class II molecule expression, which, in turn, enhance Ag presentation to CD4+ T cells. This is in contrast to one report, in which the role of p38 in MHC class II–mediated Ag presentation by multiple myeloma patient DCs was studied. In that system, p38 activation inhibited Ag presentation by MHC class II molecules, concomitant with reduced costimulatory molecules and MHC class II expression on the cell surface (54).

We have done extensive analyses on signal-transduction pathways that can regulate lipid Ag presentation by CD1d. It is well known that viruses (along with other external stimuli) activate p38 in cells (43). We analyzed the role of p38 in regulating CD1d-mediated Ag presentation following infection with vaccinia virus or vesicular stomatitis virus and found that it was inhibitory; blocking p38 actually increased Ag presentation to NKT cells (42, 43). However, this does not only occur in a virus infection. Inducing apoptosis in CD1d+ APCs stimulates p38 activation; not surprisingly, these cells are poorer stimulators of NKT cells (41). Interestingly, another group looked at Ag presentation by group 1 CD1 molecules. As we (55) observed with CD1d, p38 is inhibitory in that system as well. Notably, p38 has an NKT cell–intrinsic negative effect, because treatment of invariant NKT cells with a p38-specific inhibitor impairs their stimulation by the CD1d-binding (and NKT cell–stimulating) glycolipid α-galactosylceramide (56) or by an anti-CD3–specific mAb (57). Therefore, p38 can affect the APC and T cell sides of a host’s immune response.

As indicated above, JNK has effects on many of the same cellular functions as p38, although there is not total overlap (37). Certainly, analyses in DCs found that, like for p38, anisomycin induces JNK in human monocyte-derived DCs, although at higher concentrations (39). Unlike p38, there is no detectable JNK in human DCs (39) at baseline, and TLR4 activation does not stimulate JNK in murine DCs (45). Does JNK have any role in Ag processing and presentation? It was shown that JNK2-deficient mice generate more CD8+ T cells in response to IL-2 (58), and more antiviral CD8+ cells are found in these mice upon infection with lymphocytic choriomeningitis virus (59). This suggests that JNK can have a negative effect on MHC class I–mediated Ag presentation; alternatively (or additionally), this could be T cell intrinsic. In line with those two articles, we found that JNK2 is a negative regulator of Ag presentation by CD1d (J. Liu, R.M. Gallo, M.A. Khan, A.K. Iyer, I.A. Kratzke, and R.R. Brutkiewicz, manuscript in preparation). Studies on the JNK signaling pathway in the control of Ag presentation by classical and/or nonclassical MHC molecules are still limited.

A few studies asked whether the ERK MAPK pathway is important for MΦ or DC maturation or whether it can be activated in either cell population. For example, one study suggested that LPS or GM-CSF induces ERK in MΦs, albeit with different kinetics: the latter induces ERK activation much more quickly (5 min versus 15 min) (60). LPS activates ERK in MΦs (44, 61); however, it apparently does not do so in DCs (62). In terms of MΦ maturation, it is ERK and p38 dependent (20). In contrast, ERK promotes, but p38 impairs, the differentiation of human monocytes into DCs (40). We (43) reported that, in the context of lipid Ag presentation by CD1d, ERK is a positive regulator.

As indicated above, a number of cytokines can activate MAPK signaling, with an impact on APC-maturation or Ag-presentation abilities. In some cases, such as with TGF-β, although the cytokine can activate MAPKs, which negatively regulate CD1d-mediated Ag presentation (4143) (J. Liu et al., manuscript in preparation), the ultimate effect on Ag presentation by CD1d in the TGF-β model appears to be (at least) p38 independent (21).

The protein kinase C (PKC) family members are Ser/Thr kinases that consist of three main subgroups: conventional/classical (PKCα, β [I and II], and γ); atypical (PKC ζ and λ/ι); and novel (δ, ε, and θ) (reviewed in Ref. 63). Within these subgroups are 10 kinases that play distinct roles in the regulation of gene expression and cell proliferation. The activation of PKCs modifies them from a quiescent cytosolic form to an active membrane-associated form (64). Beyond their role as cytoplasmic signal-transduction molecules, there is evidence to suggest that they can also serve as nuclear kinases. In terms of the control of Ag presentation, PKC isoforms were shown to promote Ag presentation by MHC class II molecules. In particular, the use of PKC activators, such as bryostatin, which activates PKC-α, δ, and ι, or PKC activation by phorbol esters and ionomycin increases the surface expression of MHC class II molecules and, thereby, increases Ag presentation (27, 65, 66). The use of PKC-specific (i.e., PKC-α and/or PKC-δ) inhibitors by our laboratory (67) and other investigators (23, 27) further supports the positive correlation between PKC-δ activation and Ag presentation by MHC class II molecules. Interestingly, we (67) found that Ag presentation by CD1d, an MHC class I–like molecule that traffics intracellularly more like MHC class II molecules, is promoted by PKC-δ. In contrast to MHC class II and CD1d, Ag presentation by MHC class I molecules is not impacted by PKC-δ (27, 67).

In general, when one thinks about what constitutes the innate immune response, the first thing that often comes to mind is a response via TLRs (reviewed in Ref. 68). The TLR family of molecules consists of up to 13 structurally similar molecules in mammals that are homologs of the Drosophila toll gene product (69). TLRs are molecules on the cell surface and/or in intracellular (e.g., endocytic) compartments (i.e., TLR3, TLR7/8, TLR9) to which microbial or viral products bind; this results in the activation of various cell signaling pathways, including MAPK and other kinases (70). The majority of TLRs (TLR3 is the exception) use the MyD88 adaptor molecule for signaling down the TLR-activation cascade (68, 70). These responses can have important effects on Ag presentation by classical MHC molecules (17), as well as by CD1d (7176). Globally, the binding of a ligand to its specific TLR can regulate immunodominance; this was shown in the context of the Toxoplasma gondii–encoded protein, profilin, via MHC class II molecules (77). In contrast, TLR7/8 agonists can impair the differentiation of monocytes into DCs (78). Thus, activation via TLRs can promote (or inhibit) APC function.

In terms of MHC class I–mediated Ag presentation, TLR engagement can enhance (or have a minimal effect on) overall surface MHC class I expression (79, 80). However, ligands for TLR2 and other TLRs can impair conventional Ag presentation by MHC class I (80, 81). TLR signals can also have very important regulatory (albeit not direct) roles in triggering the delivery of MHC class I molecules to phagosomes for cross-presentation. These signals result in the IκB-kinase 2–mediated phosphorylation of phagosome-associated SNAP23, which stabilizes SNARE complexes, ultimately facilitating cross-presentation (11). Similar to endogenous Ag presentation by MHC class I, cross-presentation can also be reduced upon TLR engagement (7, 15, 18). Alternatively, cross-presentation can be enhanced via the binding of TLR2-specific (13, 82), TLR4-specific (18), TLR7-specific (8), or TLR9-specific (83) agonists. Differences in terms of the activation versus inhibition of cross-presentation are likely due to the timing of APC exposure to the TLR ligands compared with the cross-presented Ags.

Ag presentation by MHC class II molecules is also differentially affected by the engagement of distinct TLRs. Interestingly, in some cases, it seems to be a means of immune evasion by a pathogen. For example, 19- and 24-kDa lipoproteins from Mycobacterium tuberculosis can inhibit MHC class II expression and Ag processing via TLR2 signaling (25, 84, 85). In contrast, a variety of TLR ligands (including those for TLR2) can upregulate MHC class II molecules on microglia (29). Ligands for TLR1/2, TLR4, TLR7, and TLR9 were shown to enhance the ability of APCs to present Ag-85B of bacillus Calmette-Guérin to CD4+ T cells specific for that Ag via the upregulation of MHC class II molecules (86). Moreover, the stimulation of TLR signaling and delivery of a TLR-specific ligand (in this case, the TLR4 ligand LPS) into phagosomes can contribute to the generation of peptide/MHC class II complexes; this is as a means to segregate self-peptides versus nonself-peptides in a phagosome-autonomous manner (22). This delivery of TLR4 ligands is due to adaptor protein-3–dependent transport of TLR4 from endosomes to phagosomes (87). Sometimes, MHC class II–mediated responses, in this case, flagellin-specific CD4+ T cell responses, can be enhanced in a TLR5-dependent (but nonconventional TLR signaling pathway) manner (26). In that study, DCs from MyD88-deficient mice increased flagellin-specific CD4+ T cells in a TLR5-dependent manner that was comparable to DCs from wild-type mice (26). This response is regulated by CD103CD11b+ DCs (88). Type I IFNs can work with TLR ligand–mediated signals to generate type B peptide/MHC class II complexes (pMHCs); type B pMHCs are formed in early endosomes from exogenous peptides (89). In fact, type I IFNs are very important for such peptide generation because DCs deficient in the receptor for type I IFNs are impaired in their ability to generate type B pMHCs (89). However, in the context of DC maturation, although TLR ligands can inhibit MHC class II synthesis and presence in intracellular compartments, type I IFNs can prevent this from occurring (30).

The activation of TLR signaling pathways by TLR-specific ligands also was investigated in terms of its effect on the CD1d/NKT cell axis. Mimicking APC stimulation of NKT cells (i.e., a panel of murine NKT cell hybridomas) using anti-CD3 and IFN-α upregulates TLRs on the cell surface (75). Moreover, the exposure of NKT cells to a variety of TLR ligands enhances NKT cell production of IFN-γ, IL-4, and TNF-α (75). However, another study indicated that, although human NKT cells express all TLRs (except TLR8), they are not activated when directly exposed to TLR ligands; yet, they are stimulated when TLR ligands are added to total PBMCs (73). The differences could simply be due to the fact that these studies analyzed mouse NKT cell hybridomas (75) as opposed to normal human NKT cells from PBMCs (73). Culture of murine mononuclear cells with the CD1d-binding glycolipid α-galactosylceramide and polyinosinic-polycytidylic acid (a TLR3 ligand) resulted in NKT cell activation in a model of airway inflammation (76). Certainly, the effects observed in that study could be NKT cell and/or APC specific. Murine bone marrow–derived DCs exposed to LPS or infected with Salmonella typhimurium were able to stimulate NKT cells at a high level. This suggests that APC TLR4 signaling enhanced Ag presentation by CD1d molecules (71). Additionally, TLR4 was shown to work with Nod1 and Nod2, two members of the Nod-like receptor family that are cytosolic pattern-recognition receptors. In that situation, LPS treatment of bone marrow–derived DCs resulted in IFN-γ production by NKT cells (74). An in vivo infection with S. typhimurium (which contains LPS) can activate invariant NKT cells (71, 72) but does so without the need for a CD1d-presented lipid Ag (72).

The JAK/STAT signaling pathway is activated by most cytokines involved in the development and regulation of the host’s immune response (90). There are four receptor-associated JAKs that, upon phosphorylation of the receptor they are bound to, recruit one of seven STATs to the receptor to be phosphorylated by that JAK. This process results in the dimerization of the p-STATs, which are translocated into the nucleus where they regulate the expression of a variety of genes (91).

JAK/STAT signaling upon activation by IFN-γ is critical for MHC gene expression and, ultimately, expression of MHC class I and II molecules on the cell surface (90, 91). Of importance, it was shown that p-STAT1 facilitates human MHC locus chromatin remodeling as a first step for the subsequent expression of HLA genes (92). Impairing the ability of IFN-γ to stimulate JAK/STAT signaling and, thereby, preventing MHC gene expression, is one mechanism by which viruses can evade recognition by the host’s immune response (16). For example, MHC class I and/or class II molecules can be targeted by herpesviruses (19, 28, 93) or influenza virus (31). In each of these cases, it is likely that a virus-encoded protein(s) prevented IFN-γ–induced activation of the JAK/STAT pathway. Similarly, immune evasion by solid tumors can be due to an impairment of JAK/STAT signaling that prevents the upregulation of MHC class I molecules (12, 14) or TAP1 expression (9).

In contrast to the immune-evasion examples presented above, activation of JAK/STAT signaling can have beneficial effects. For example, IL-10, which activates a JAK1/STAT3 complex, inhibits DC maturation by mesenchymal stem cells (94). An example for which this could be important is in the prevention of NKT cell–mediated colitis. Here, cross-linking CD1d on colonic epithelial cells results in STAT3 activation; the transcription of the il-10 gene (by STAT3) and consequent IL-10 production control inflammation in those cells (95). Recently, we (96) showed that STAT3 is essential for CD1d-mediated Ag presentation because of its ability to regulate the transcription of UDP glucose ceramide glycosyltransferase, an enzyme involved in the first step of glycosphingolipid biosynthesis, from which the natural ligands of CD1d are derived. The critical nature of STAT3 in the CD1d/NKT cell axis is evident in patients with loss-of-function mutations in STAT3. Those patients have a significantly reduced number of NKT cells (97).

Rho GTPases are well known for mediating intracellular protein traffic (reviewed in Ref. 98). This is due to their control over the generation of F-actin. Thus, Rho GTPases activate the Rho kinase (ROCK) which then phosphorylates the LIM kinase, which then activates cofilin. Normally, cofilin, in its nonphosphorylated form, prevents the polymerization of actin. The phosphorylation of cofilin by LIM kinase permits F-actin formation (99, 100). We found that F-actin actually impairs Ag presentation by CD1d (101). When we disrupted the actin cytoskeleton with cytochalasin D, Ag presentation was enhanced. Thus, ROCK is a negative regulator of CD1d-mediated Ag presentation. Interestingly, we found that ROCK actually promoted Ag presentation by MHC class II molecules (101). This was another example in which we have found specific cell signaling pathways that differentially regulate Ag presentation by MHC class II versus CD1d (21, 96, 101).

Knowing that ROCK impairs Ag presentation by CD1d via the polymerization of actin is only part of the mechanism by which this occurs. How does actin actually do it? Recently, it has been reported that actin segregates CD1d nanoclusters on the cell surface via direct interaction between actin and the CD1d cytoplasmic tail (102). This interaction keeps them at a certain density on the surface. Allowing the formation of larger nanoclusters (by blocking the ability of CD1d’s cytoplasmic tail to bind to actin) results in enhanced NKT cell activation—exactly the same observation we made when the actin cytoskeleton was disrupted in our system by cytochalasin D (101).

For the most part, cell signaling pathways appear to be important in inflammatory diseases (including cancer), which have a clear–or likely–immune component, where Ag processing and presentation would come into play. Of the MAPK, upstream ERK pathway components (i.e., Ras-Raf-ERK) are more involved. Either Ras or Raf contribute to malignant transformation and are thereby targeted with Ras- or Raf-specific inhibitors (103106). Moreover, blocking ERK in esophageal and gastric cancers, or in melanoma (in the context of immunotherapy), results in an increase in MHC class I molecules (107109).

For the p38 MAPK, inflammation was shown to increase tumor-induced (and immunosuppressive) myeloid-derived suppressor cells; the activation of p38 is believed to be important for their survival (110). For the treatment of rheumatoid arthritis, p38 inhibitors have been considered (111). Moreover, p38 is also believed to be a culprit in the development of acquired immune deficiency syndrome and HIV-associated neurocognitive disorders in HIV patients, which could have an Ag presentation component (112).

An important aspect of p38 signaling needs to be taken into account when considering using inhibitors against that MAPK: there is reciprocal cross-talk between p38 and STAT3 [reviewed in (113)]. In the context of the CD1d/NKT cell axis, this could be critical in the disease that one is attempting to mitigate, as p38 is a negative (whereas STAT3 is a positive) regulator of lipid Ag presentation by CD1d (4143, 96, 97, 101).

The JAK/STAT pathway (in particular, STAT3) is also important in cancer and inflammation. In a recent study of patients with nonrefractory Hodgkin’s lymphoma being treated using a programmed cell death-1–blockade immunotherapy paradigm, p-STAT3 was detected in the nucleus of Reed-Sternberg cells (the presence of which is necessary for the diagnosis of Hodgkin’s lymphoma) (114). STAT3 is activated in Behçet’s disease, an inflammatory disorder resulting in vasculitis (115). In contrast, there appears to be attenuated IFN-α–induced STAT3 signaling in DCs from patients with Crohn’s disease, and IL-10 induces enhanced STAT3 activation, which could impact the DC’s ability to present Ag (116). Relating Crohn’s disease effects to the various cell signaling pathways in this Brief Review, there appears to be an association with an ICOSL loss-of-function mutation resulting in reduced cell signaling in these patients (117); this likely impacts immune homeostasis.

Lastly, signaling via TLRs has been predominantly associated with infectious diseases (118124); however, a variety of single-nucleotide polymorphisms in human TLRs have not only been associated with infectious and inflammatory (including autoimmune) diseases, but also with cancer (121, 123126). As such, TLRs have been looked at as potential targets for immune-based therapy against infectious diseases (118, 119), as well as sepsis-associated pathology (118). Moreover, another approach that is being considered is the specific targeting of TLR-associated adaptors that are negative regulators of TLR signaling (127). This is reminiscent of the CTLA-4 and inhibitory receptor programmed cell death-1 targeting of antitumor T cells that has recently shown promise in clinical trials with cancer patients (128, 129). This approach effectively removes inhibitory signals coming from the APCs to the effector T cells.

Although cell signaling pathways have been studied for a number of years, very little has been focused on Ag processing and presentation and how they affect APCs and/or the T cells that recognize them. Nonetheless, Fig. 2 summarizes what I described in this Brief Review in terms of how these cell signaling pathways affect MHC class I, MHC class II, and/or CD1d. To help the readers, I also included a table (Table I), indicating the reports cited in this study, that have studied these specific cell signaling pathways and Ag presentation. As is clear from the work done so far, the cell signaling pathways described above have at least some impact on various components of a host’s immune response; these could potentially be exploited for adding new weapons to the arsenal against infectious and autoimmune diseases, as well as cancer. We have just begun to scratch the surface.

FIGURE 2.

Summary of the known effects of cell signaling pathways on Ag presentation by MHC class I, MHC class II, and CD1d molecules. The effects are indicated as a traffic light analogy: green is a positive (or upregulating) effect, red is a negative (or downregulating) effect; those pathways in the yellow light suggest some ambiguity for the effects of those pathways (e.g., some are positive, and some are negative; it depends on the context).

FIGURE 2.

Summary of the known effects of cell signaling pathways on Ag presentation by MHC class I, MHC class II, and CD1d molecules. The effects are indicated as a traffic light analogy: green is a positive (or upregulating) effect, red is a negative (or downregulating) effect; those pathways in the yellow light suggest some ambiguity for the effects of those pathways (e.g., some are positive, and some are negative; it depends on the context).

Close modal
Table I.
Reports addressing Ag presentation via cell signaling pathways
Effects on Ag Presentation By:
Cell Signaling PathwayMHC Class IMHC Class IICD1d
p38 7, 4749, 51  5254  21, 42, 43  
ERK 47, 48  47, 48  43  
JNK 58, 59   Liu et al.a 
PKC  23, 27, 6567  67  
ROCK  101  101  
TLR 7, 8, 13, 15, 17, 18, 51, 7983  17, 22, 25, 26, 30, 77, 8486, 88, 89  7176  
JAK/STAT 9, 12, 14, 16, 19, 28, 31, 9093  16, 19, 28, 31, 9093  96, 97  
Effects on Ag Presentation By:
Cell Signaling PathwayMHC Class IMHC Class IICD1d
p38 7, 4749, 51  5254  21, 42, 43  
ERK 47, 48  47, 48  43  
JNK 58, 59   Liu et al.a 
PKC  23, 27, 6567  67  
ROCK  101  101  
TLR 7, 8, 13, 15, 17, 18, 51, 7983  17, 22, 25, 26, 30, 77, 8486, 88, 89  7176  
JAK/STAT 9, 12, 14, 16, 19, 28, 31, 9093  16, 19, 28, 31, 9093  96, 97  

Reference numbers cited in this review that describe a role for the various cell signaling pathways in Ag presentation.

a

J. Liu et al., manuscript in preparation.

I thank the members of my laboratory, past and present, who have made many important contributions to our understanding of how cell signaling pathways regulate Ag presentation by CD1d. I thank Jean Liu and Abhirami Iyer for careful reading of the manuscript and I also thank Abhirami Iyer for the idea regarding a summary figure for this review.

This work was supported by grants from the National Institutes of Health and Department of Defense.

Abbreviations used in this article:

DC

dendritic cell

macrophage

PKC

protein kinase C.

1
Blum
J. S.
,
Wearsch
P. A.
,
Cresswell
P.
.
2013
.
Pathways of antigen processing.
Annu. Rev. Immunol.
31
:
443
473
.
2
Springer
S.
2015
.
Transport and quality control of MHC class I molecules in the early secretory pathway.
Curr. Opin. Immunol.
34
:
83
90
.
3
Mintern
J. D.
,
Macri
C.
,
Villadangos
J. A.
.
2015
.
Modulation of antigen presentation by intracellular trafficking.
Curr. Opin. Immunol.
34
:
16
21
.
4
Adiko
A. C.
,
Babdor
J.
,
Gutiérrez-Martínez
E.
,
Guermonprez
P.
,
Saveanu
L.
.
2015
.
Intracellular transport routes for MHC I and their relevance for antigen cross-presentation.
Front. Immunol.
6
:
335
.
5
McEwen-Smith
R. M.
,
Salio
M.
,
Cerundolo
V.
.
2015
.
CD1d-dependent endogenous and exogenous lipid antigen presentation.
Curr. Opin. Immunol.
34
:
116
125
.
6
Ackerman
A. L.
,
Cresswell
P.
.
2003
.
Regulation of MHC class I transport in human dendritic cells and the dendritic-like cell line KG-1.
J. Immunol.
170
:
4178
4188
.
7
Aleyas
A. G.
,
Han
Y. W.
,
Patil
A. M.
,
Kim
S. B.
,
Kim
K.
,
Eo
S. K.
.
2012
.
Impaired cross-presentation of CD8α+ CD11c+ dendritic cells by Japanese encephalitis virus in a TLR2/MyD88 signal pathway-dependent manner.
Eur. J. Immunol.
42
:
2655
2666
.
8
Crespo
M. I.
,
Zacca
E. R.
,
Núñez
N. G.
,
Ranocchia
R. P.
,
Maccioni
M.
,
Maletto
B. A.
,
Pistoresi-Palencia
M. C.
,
Morón
G.
.
2013
.
TLR7 triggering with polyuridylic acid promotes cross-presentation in CD8α+ conventional dendritic cells by enhancing antigen preservation and MHC class I antigen permanence on the dendritic cell surface.
J. Immunol.
190
:
948
960
.
9
Heise
R.
,
Amann
P. M.
,
Ensslen
S.
,
Marquardt
Y.
,
Czaja
K.
,
Joussen
S.
,
Beer
D.
,
Abele
R.
,
Plewnia
G.
,
Tampé
R.
, et al
.
2016
.
Interferon alpha signalling and its relevance for the upregulatory effect of transporter proteins associated with antigen processing (TAP) in patients with malignant melanoma.
PLoS One
11
:
e0146325
.
10
MacAry
P. A.
,
Lindsay
M.
,
Scott
M. A.
,
Craig
J. I.
,
Luzio
J. P.
,
Lehner
P. J.
.
2001
.
Mobilization of MHC class I molecules from late endosomes to the cell surface following activation of CD34-derived human Langerhans cells.
Proc. Natl. Acad. Sci. USA
98
:
3982
3987
.
11
Nair-Gupta
P.
,
Baccarini
A.
,
Tung
N.
,
Seyffer
F.
,
Florey
O.
,
Huang
Y.
,
Banerjee
M.
,
Overholtzer
M.
,
Roche
P. A.
,
Tampé
R.
, et al
.
2014
.
TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation.
Cell
158
:
506
521
.
12
Rodríguez
T.
,
Méndez
R.
,
Del Campo
A.
,
Jiménez
P.
,
Aptsiauri
N.
,
Garrido
F.
,
Ruiz-Cabello
F.
.
2007
.
Distinct mechanisms of loss of IFN-gamma mediated HLA class I inducibility in two melanoma cell lines.
BMC Cancer
7
:
34
.
13
Shen
K. Y.
,
Song
Y. C.
,
Chen
I. H.
,
Leng
C. H.
,
Chen
H. W.
,
Li
H. J.
,
Chong
P.
,
Liu
S. J.
.
2014
.
Molecular mechanisms of TLR2-mediated antigen cross-presentation in dendritic cells.
J. Immunol.
192
:
4233
4241
.
14
Svane
I. M.
,
Engel
A. M.
,
Nielsen
M.
,
Werdelin
O.
.
1997
.
Interferon-gamma-induced MHC class I expression and defects in Jak/Stat signalling in methylcholanthrene-induced sarcomas.
Scand. J. Immunol.
46
:
379
387
.
15
Weck
M. M.
,
Grünebach
F.
,
Werth
D.
,
Sinzger
C.
,
Bringmann
A.
,
Brossart
P.
.
2007
.
TLR ligands differentially affect uptake and presentation of cellular antigens.
Blood
109
:
3890
3894
.
16
Zhou
F.
2009
.
Molecular mechanisms of viral immune evasion proteins to inhibit MHC class I antigen processing and presentation.
Int. Rev. Immunol.
28
:
376
393
.
17
Nair
P.
,
Amsen
D.
,
Blander
J. M.
.
2011
.
Co-ordination of incoming and outgoing traffic in antigen-presenting cells by pattern recognition receptors and T cells.
Traffic
12
:
1669
1676
.
18
Wagner
C. S.
,
Cresswell
P.
.
2012
.
TLR and nucleotide-binding oligomerization domain-like receptor signals differentially regulate exogenous antigen presentation.
J. Immunol.
188
:
686
693
.
19
Abendroth
A.
,
Slobedman
B.
,
Lee
E.
,
Mellins
E.
,
Wallace
M.
,
Arvin
A. M.
.
2000
.
Modulation of major histocompatibility class II protein expression by varicella-zoster virus.
J. Virol.
74
:
1900
1907
.
20
Andreae
S.
,
Buisson
S.
,
Triebel
F.
.
2003
.
MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223).
Blood
102
:
2130
2137
.
21
Bailey
J. C.
,
Iyer
A. K.
,
Renukaradhya
G. J.
,
Lin
Y.
,
Nguyen
H.
,
Brutkiewicz
R. R.
.
2014
.
Inhibition of CD1d-mediated antigen presentation by the transforming growth factor-β/Smad signalling pathway.
Immunology
143
:
679
691
.
22
Blander
J. M.
,
Medzhitov
R.
.
2006
.
Toll-dependent selection of microbial antigens for presentation by dendritic cells.
Nature
440
:
808
812
.
23
Chen
Y. W.
,
Lang
M. L.
,
Wade
W. F.
.
2004
.
Protein kinase C-alpha and -delta are required for FcalphaR (CD89) trafficking to MHC class II compartments and FcalphaR-mediated antigen presentation.
Traffic
5
:
577
594
.
24
Delamarre
L.
,
Holcombe
H.
,
Mellman
I.
.
2003
.
Presentation of exogenous antigens on major histocompatibility complex (MHC) class I and MHC class II molecules is differentially regulated during dendritic cell maturation.
J. Exp. Med.
198
:
111
122
.
25
Gehring
A. J.
,
Dobos
K. M.
,
Belisle
J. T.
,
Harding
C. V.
,
Boom
W. H.
.
2004
.
Mycobacterium tuberculosis LprG (Rv1411c): a novel TLR-2 ligand that inhibits human macrophage class II MHC antigen processing.
J. Immunol.
173
:
2660
2668
.
26
Letran
S. E.
,
Lee
S. J.
,
Atif
S. M.
,
Uematsu
S.
,
Akira
S.
,
McSorley
S. J.
.
2011
.
TLR5 functions as an endocytic receptor to enhance flagellin-specific adaptive immunity.
Eur. J. Immunol.
41
:
29
38
.
27
Majewski
M.
,
Bose
T. O.
,
Sillé
F. C.
,
Pollington
A. M.
,
Fiebiger
E.
,
Boes
M.
.
2007
.
Protein kinase C delta stimulates antigen presentation by Class II MHC in murine dendritic cells.
Int. Immunol.
19
:
719
732
.
28
Miller
D. M.
,
Rahill
B. M.
,
Boss
J. M.
,
Lairmore
M. D.
,
Durbin
J. E.
,
Waldman
J. W.
,
Sedmak
D. D.
.
1998
.
Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway.
J. Exp. Med.
187
:
675
683
.
29
Olson
J. K.
,
Miller
S. D.
.
2004
.
Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs.
J. Immunol.
173
:
3916
3924
.
30
Simmons
D. P.
,
Wearsch
P. A.
,
Canaday
D. H.
,
Meyerson
H. J.
,
Liu
Y. C.
,
Wang
Y.
,
Boom
W. H.
,
Harding
C. V.
.
2012
.
Type I IFN drives a distinctive dendritic cell maturation phenotype that allows continued class II MHC synthesis and antigen processing.
J. Immunol.
188
:
3116
3126
.
31
Uetani
K.
,
Hiroi
M.
,
Meguro
T.
,
Ogawa
H.
,
Kamisako
T.
,
Ohmori
Y.
,
Erzurum
S. C.
.
2008
.
Influenza A virus abrogates IFN-gamma response in respiratory epithelial cells by disruption of the Jak/Stat pathway.
Eur. J. Immunol.
38
:
1559
1573
.
32
Kain
L.
,
Costanzo
A.
,
Webb
B.
,
Holt
M.
,
Bendelac
A.
,
Savage
P. B.
,
Teyton
L.
.
2015
.
Endogenous ligands of natural killer T cells are alpha-linked glycosylceramides.
Mol. Immunol.
68
(
2 Pt A
):
94
97
.
33
Van Rhijn
I.
,
Godfrey
D. I.
,
Rossjohn
J.
,
Moody
D. B.
.
2015
.
Lipid and small-molecule display by CD1 and MR1.
Nat. Rev. Immunol.
15
:
643
654
.
34
Le Bourhis
L.
,
Mburu
Y. K.
,
Lantz
O.
.
2013
.
MAIT cells, surveyors of a new class of antigen: development and functions.
Curr. Opin. Immunol.
25
:
174
180
.
35
McWilliam
H. E.
,
Birkinshaw
R. W.
,
Villadangos
J. A.
,
McCluskey
J.
,
Rossjohn
J.
.
2015
.
MR1 presentation of vitamin B-based metabolite ligands.
Curr. Opin. Immunol.
34
:
28
34
.
36
Arthur
J. S.
,
Ley
S. C.
.
2013
.
Mitogen-activated protein kinases in innate immunity.
Nat. Rev. Immunol.
13
:
679
692
.
37
Rincón
M.
,
Flavell
R. A.
,
Davis
R. A.
.
2000
.
The JNK and P38 MAP kinase signaling pathways in T cell-mediated immune responses.
Free Radic. Biol. Med.
28
:
1328
1337
.
38
Lu
H. T.
,
Yang
D. D.
,
Wysk
M.
,
Gatti
E.
,
Mellman
I.
,
Davis
R. J.
,
Flavell
R. A.
.
1999
.
Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice.
EMBO J.
18
:
1845
1857
.
39
Bunyard
P.
,
Handley
M.
,
Pollara
G.
,
Rutault
K.
,
Wood
I.
,
Chaudry
M.
,
Alderman
C.
,
Foreman
J.
,
Katz
D. R.
,
Chain
B. M.
.
2003
.
Ribotoxic stress activates p38 and JNK kinases and modulates the antigen-presenting activity of dendritic cells.
Mol. Immunol.
39
:
815
827
.
40
Xie
J.
,
Qian
J.
,
Yang
J.
,
Wang
S.
,
Freeman
M. E.
 III
,
Yi
Q.
.
2005
.
Critical roles of Raf/MEK/ERK and PI3K/AKT signaling and inactivation of p38 MAP kinase in the differentiation and survival of monocyte-derived immature dendritic cells.
Exp. Hematol.
33
:
564
572
.
41
Khan
M. A.
,
Sriram
V.
,
Renukaradhya
G. J.
,
Du
W.
,
Gervay-Hague
J.
,
Brutkiewicz
R. R.
.
2008
.
Apoptosis-induced inhibition of CD1d-mediated antigen presentation: different roles for caspases and signal transduction pathways.
Immunology
125
:
80
90
.
42
Renukaradhya
G. J.
,
Khan
M. A.
,
Shaji
D.
,
Brutkiewicz
R. R.
.
2008
.
Vesicular stomatitis virus matrix protein impairs CD1d-mediated antigen presentation through activation of the p38 MAPK pathway.
J. Virol.
82
:
12535
12542
.
43
Renukaradhya
G. J.
,
Webb
T. J.
,
Khan
M. A.
,
Lin
Y. L.
,
Du
W.
,
Gervay-Hague
J.
,
Brutkiewicz
R. R.
.
2005
.
Virus-induced inhibition of CD1d1-mediated antigen presentation: reciprocal regulation by p38 and ERK.
J. Immunol.
175
:
4301
4308
.
44
Ardeshna
K. M.
,
Pizzey
A. R.
,
Devereux
S.
,
Khwaja
A.
.
2000
.
The PI3 kinase, p38 SAP kinase, and NF-kappaB signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells.
Blood
96
:
1039
1046
.
45
Rescigno
M.
,
Martino
M.
,
Sutherland
C. L.
,
Gold
M. R.
,
Ricciardi-Castagnoli
P.
.
1998
.
Dendritic cell survival and maturation are regulated by different signaling pathways.
J. Exp. Med.
188
:
2175
2180
.
46
Jörgl
A.
,
Platzer
B.
,
Taschner
S.
,
Heinz
L. X.
,
Höcher
B.
,
Reisner
P. M.
,
Göbel
F.
,
Strobl
H.
.
2007
.
Human Langerhans-cell activation triggered in vitro by conditionally expressed MKK6 is counterregulated by the downstream effector RelB.
Blood
109
:
185
193
.
47
Bharadwaj
U.
,
Zhang
R.
,
Yang
H.
,
Li
M.
,
Doan
L. X.
,
Chen
C.
,
Yao
Q.
.
2005
.
Effects of cyclophilin A on myeloblastic cell line KG-1 derived dendritic like cells (DLC) through p38 MAP kinase activation.
J. Surg. Res.
127
:
29
38
.
48
Seshasayee
D.
,
Wang
H.
,
Lee
W. P.
,
Gribling
P.
,
Ross
J.
,
Van Bruggen
N.
,
Carano
R.
,
Grewal
I. S.
.
2004
.
A novel in vivo role for osteoprotegerin ligand in activation of monocyte effector function and inflammatory response.
J. Biol. Chem.
279
:
30202
30209
.
49
Yu
Q.
,
Kovacs
C.
,
Yue
F. Y.
,
Ostrowski
M. A.
.
2004
.
The role of the p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and phosphoinositide-3-OH kinase signal transduction pathways in CD40 ligand-induced dendritic cell activation and expansion of virus-specific CD8+ T cell memory responses.
J. Immunol.
172
:
6047
6056
.
50
Hansen
S. G.
,
Sacha
J. B.
,
Hughes
C. M.
,
Ford
J. C.
,
Burwitz
B. J.
,
Scholz
I.
,
Gilbride
R. M.
,
Lewis
M. S.
,
Gilliam
A. N.
,
Ventura
A. B.
, et al
.
2013
.
Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms.
Science
340
:
1237874
.
51
Turnis
M. E.
,
Song
X. T.
,
Bear
A.
,
Foster
A. E.
,
Gottschalk
S.
,
Brenner
M. K.
,
Chen
S. Y.
,
Rooney
C. M.
.
2010
.
IRAK-M removal counteracts dendritic cell vaccine deficits in migration and longevity.
J. Immunol.
185
:
4223
4232
.
52
Park
S. Y.
,
Kim
Y.
.
2009
.
Surfactin inhibits immunostimulatory function of macrophages through blocking NK-kappaB, MAPK and Akt pathway.
Int. Immunopharmacol.
9
:
886
893
.
53
Palová-Jelínková
L.
,
Rozková
D.
,
Pecharová
B.
,
Bártová
J.
,
Sedivá
A.
,
Tlaskalová-Hogenová
H.
,
Spísek
R.
,
Tucková
L.
.
2005
.
Gliadin fragments induce phenotypic and functional maturation of human dendritic cells.
J. Immunol.
175
:
7038
7045
.
54
Wang
S.
,
Hong
S.
,
Yang
J.
,
Qian
J.
,
Zhang
X.
,
Shpall
E.
,
Kwak
L. W.
,
Yi
Q.
.
2006
.
Optimizing immunotherapy in multiple myeloma: Restoring the function of patients’ monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in progenitor cells.
Blood
108
:
4071
4077
.
55
Gagliardi
M. C.
,
Teloni
R.
,
Giannoni
F.
,
Mariotti
S.
,
Remoli
M. E.
,
Sargentini
V.
,
Videtta
M.
,
Pardini
M.
,
De Libero
G.
,
Coccia
E. M.
,
Nisini
R.
.
2009
.
Mycobacteria exploit p38 signaling to affect CD1 expression and lipid antigen presentation by human dendritic cells.
Infect. Immun.
77
:
4947
4952
.
56
Kawano
T.
,
Cui
J.
,
Koezuka
Y.
,
Toura
I.
,
Kaneko
Y.
,
Motoki
K.
,
Ueno
H.
,
Nakagawa
R.
,
Sato
H.
,
Kondo
E.
, et al
.
1997
.
CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides.
Science
278
:
1626
1629
.
57
Stuart
J. K.
,
Bisch
S. P.
,
Leon-Ponte
M.
,
Hayatsu
J.
,
Mazzuca
D. M.
,
Maleki Vareki
S.
,
Haeryfar
S. M.
.
2010
.
Negative modulation of invariant natural killer T cell responses to glycolipid antigens by p38 MAP kinase.
Int. Immunopharmacol.
10
:
1068
1076
.
58
Conze
D.
,
Krahl
T.
,
Kennedy
N.
,
Weiss
L.
,
Lumsden
J.
,
Hess
P.
,
Flavell
R. A.
,
Le Gros
G.
,
Davis
R. J.
,
Rincón
M.
.
2002
.
c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation.
J. Exp. Med.
195
:
811
823
.
59
Arbour
N.
,
Naniche
D.
,
Homann
D.
,
Davis
R. J.
,
Flavell
R. A.
,
Oldstone
M. B.
.
2002
.
c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 signaling pathways have divergent roles in CD8(+) T cell-mediated antiviral immunity.
J. Exp. Med.
195
:
801
810
.
60
Valledor
A. F.
,
Comalada
M.
,
Xaus
J.
,
Celada
A.
.
2000
.
The differential time-course of extracellular-regulated kinase activity correlates with the macrophage response toward proliferation or activation.
J. Biol. Chem.
275
:
7403
7409
.
61
Monick
M. M.
,
Carter
A. B.
,
Flaherty
D. M.
,
Peterson
M. W.
,
Hunninghake
G. W.
.
2000
.
Protein kinase C zeta plays a central role in activation of the p42/44 mitogen-activated protein kinase by endotoxin in alveolar macrophages.
J. Immunol.
165
:
4632
4639
.
62
Häcker
H.
,
Mischak
H.
,
Häcker
G.
,
Eser
S.
,
Prenzel
N.
,
Ullrich
A.
,
Wagner
H.
.
1999
.
Cell type-specific activation of mitogen-activated protein kinases by CpG-DNA controls interleukin-12 release from antigen-presenting cells.
EMBO J.
18
:
6973
6982
.
63
Lim
P. S.
,
Sutton
C. R.
,
Rao
S.
.
2015
.
Protein kinase C in the immune system: from signalling to chromatin regulation.
Immunology
146
:
508
522
.
64
Igumenova
T. I.
2015
.
Dynamics and membrane interactions of protein kinase C.
Biochemistry
54
:
4953
4968
.
65
Do
Y.
,
Hegde
V. L.
,
Nagarkatti
P. S.
,
Nagarkatti
M.
.
2004
.
Bryostatin-1 enhances the maturation and antigen-presenting ability of murine and human dendritic cells.
Cancer Res.
64
:
6756
6765
.
66
Zhao
D.
,
Amria
S.
,
Hossain
A.
,
Sundaram
K.
,
Komlosi
P.
,
Nagarkatti
M.
,
Haque
A.
.
2011
.
Enhancement of HLA class II-restricted CD4+ T cell recognition of human melanoma cells following treatment with bryostatin-1.
Cell. Immunol.
271
:
392
400
.
67
Brutkiewicz
R. R.
,
Willard
C. A.
,
Gillett-Heacock
K. K.
,
Pawlak
M. R.
,
Bailey
J. C.
,
Khan
M. A.
,
Nagala
M.
,
Du
W.
,
Gervay-Hague
J.
,
Renukaradhya
G. J.
.
2007
.
Protein kinase C delta is a critical regulator of CD1d-mediated antigen presentation.
Eur. J. Immunol.
37
:
2390
2395
.
68
Kawai
T.
,
Akira
S.
.
2011
.
Toll-like receptors and their crosstalk with other innate receptors in infection and immunity.
Immunity
34
:
637
650
.
69
Lemaitre
B.
,
Nicolas
E.
,
Michaut
L.
,
Reichhart
J. M.
,
Hoffmann
J. A.
.
1996
.
The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults.
Cell
86
:
973
983
.
70
McGuire
V. A.
,
Arthur
J. S.
.
2015
.
Subverting toll-like receptor signaling by bacterial pathogens.
Front. Immunol.
6
:
607
.
71
Brigl
M.
,
Bry
L.
,
Kent
S. C.
,
Gumperz
J. E.
,
Brenner
M. B.
.
2003
.
Mechanism of CD1d-restricted natural killer T cell activation during microbial infection.
Nat. Immunol.
4
:
1230
1237
.
72
Holzapfel
K. L.
,
Tyznik
A. J.
,
Kronenberg
M.
,
Hogquist
K. A.
.
2014
.
Antigen-dependent versus -independent activation of invariant NKT cells during infection.
J. Immunol.
192
:
5490
5498
.
73
Moreno
M.
,
Mol
B. M.
,
von Mensdorff-Pouilly
S.
,
Verheijen
R. H.
,
de Jong
E. C.
,
von Blomberg
B. M.
,
van den Eertwegh
A. J.
,
Scheper
R. J.
,
Bontkes
H. J.
.
2009
.
Differential indirect activation of human invariant natural killer T cells by Toll-like receptor agonists.
Immunotherapy
1
:
557
570
.
74
Selvanantham
T.
,
Escalante
N. K.
,
Cruz Tleugabulova
M.
,
Fiévé
S.
,
Girardin
S. E.
,
Philpott
D. J.
,
Mallevaey
T.
.
2013
.
Nod1 and Nod2 enhance TLR-mediated invariant NKT cell activation during bacterial infection.
J. Immunol.
191
:
5646
5654
.
75
Villanueva
A. I.
,
Haeryfar
S. M.
,
Mallard
B. A.
,
Kulkarni
R. R.
,
Sharif
S.
.
2015
.
Functions of invariant NK T cells are modulated by TLR ligands and IFN-α.
Innate Immun.
21
:
275
288
.
76
Vultaggio
A.
,
Nencini
F.
,
Pratesi
S.
,
Petroni
G.
,
Romagnani
S.
,
Maggi
E.
.
2012
.
Poly(I:C) promotes the production of IL-17A by murine CD1d-driven invariant NKT cells in airway inflammation.
Allergy
67
:
1223
1232
.
77
Yarovinsky
F.
,
Kanzler
H.
,
Hieny
S.
,
Coffman
R. L.
,
Sher
A.
.
2006
.
Toll-like receptor recognition regulates immunodominance in an antimicrobial CD4+ T cell response.
Immunity
25
:
655
664
.
78
Assier
E.
,
Marin-Esteban
V.
,
Haziot
A.
,
Maggi
E.
,
Charron
D.
,
Mooney
N.
.
2007
.
TLR7/8 agonists impair monocyte-derived dendritic cell differentiation and maturation.
J. Leukoc. Biol.
81
:
221
228
.
79
Siddiqui
S.
,
Alatery
A.
,
Kus
A.
,
Basta
S.
.
2011
.
TLR engagement prior to virus infection influences MHC-I antigen presentation in an epitope-dependent manner as a result of nitric oxide release.
J. Leukoc. Biol.
89
:
457
468
.
80
Tobian
A. A.
,
Potter
N. S.
,
Ramachandra
L.
,
Pai
R. K.
,
Convery
M.
,
Boom
W. H.
,
Harding
C. V.
.
2003
.
Alternate class I MHC antigen processing is inhibited by Toll-like receptor signaling pathogen-associated molecular patterns: Mycobacterium tuberculosis 19-kDa lipoprotein, CpG DNA, and lipopolysaccharide.
J. Immunol.
171
:
1413
1422
.
81
Aleyas
A. G.
,
Han
Y. W.
,
George
J. A.
,
Kim
B.
,
Kim
K.
,
Lee
C. K.
,
Eo
S. K.
.
2010
.
Multifront assault on antigen presentation by Japanese encephalitis virus subverts CD8+ T cell responses.
J. Immunol.
185
:
1429
1441
.
82
Santone
M.
,
Aprea
S.
,
Wu
T. Y.
,
Cooke
M. P.
,
Mbow
M. L.
,
Valiante
N. M.
,
Rush
J. S.
,
Dougan
S.
,
Avalos
A.
,
Ploegh
H.
, et al
.
2015
.
A new TLR2 agonist promotes cross-presentation by mouse and human antigen presenting cells.
Hum. Vaccin. Immunother.
11
:
2038
2050
.
83
Kool
M.
,
Geurtsvankessel
C.
,
Muskens
F.
,
Madeira
F. B.
,
van Nimwegen
M.
,
Kuipers
H.
,
Thielemans
K.
,
Hoogsteden
H. C.
,
Hammad
H.
,
Lambrecht
B. N.
.
2011
.
Facilitated antigen uptake and timed exposure to TLR ligands dictate the antigen-presenting potential of plasmacytoid DCs.
J. Leukoc. Biol.
90
:
1177
1190
.
84
Noss
E. H.
,
Pai
R. K.
,
Sellati
T. J.
,
Radolf
J. D.
,
Belisle
J.
,
Golenbock
D. T.
,
Boom
W. H.
,
Harding
C. V.
.
2001
.
Toll-like receptor 2-dependent inhibition of macrophage class II MHC expression and antigen processing by 19-kDa lipoprotein of Mycobacterium tuberculosis.
J. Immunol.
167
:
910
918
.
85
Gehring
A. J.
,
Rojas
R. E.
,
Canaday
D. H.
,
Lakey
D. L.
,
Harding
C. V.
,
Boom
W. H.
.
2003
.
The Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits gamma interferon-regulated HLA-DR and Fc gamma R1 on human macrophages through Toll-like receptor 2.
Infect. Immun.
71
:
4487
4497
.
86
Bakhru
P.
,
Sirisaengtaksin
N.
,
Soudani
E.
,
Mukherjee
S.
,
Khan
A.
,
Jagannath
C.
.
2014
.
BCG vaccine mediated reduction in the MHC-II expression of macrophages and dendritic cells is reversed by activation of Toll-like receptors 7 and 9.
Cell. Immunol.
287
:
53
61
.
87
Mantegazza
A. R.
,
Guttentag
S. H.
,
El-Benna
J.
,
Sasai
M.
,
Iwasaki
A.
,
Shen
H.
,
Laufer
T. M.
,
Marks
M. S.
.
2012
.
Adaptor protein-3 in dendritic cells facilitates phagosomal toll-like receptor signaling and antigen presentation to CD4(+) T cells.
Immunity
36
:
782
794
.
88
Atif
S. M.
,
Uematsu
S.
,
Akira
S.
,
McSorley
S. J.
.
2014
.
CD103-CD11b+ dendritic cells regulate the sensitivity of CD4 T-cell responses to bacterial flagellin.
Mucosal Immunol.
7
:
68
77
.
89
Strong
B. S.
,
Unanue
E. R.
.
2011
.
Presentation of type B peptide-MHC complexes from hen egg white lysozyme by TLR ligands and type I IFNs independent of H2-DM regulation.
J. Immunol.
187
:
2193
2201
.
90
O’Shea
J. J.
,
Plenge
R.
.
2012
.
JAK and STAT signaling molecules in immunoregulation and immune-mediated disease.
Immunity
36
:
542
550
.
91
O’Shea
J. J.
,
Holland
S. M.
,
Staudt
L. M.
.
2013
.
JAKs and STATs in immunity, immunodeficiency, and cancer.
N. Engl. J. Med.
368
:
161
170
.
92
Christova
R.
,
Jones
T.
,
Wu
P. J.
,
Bolzer
A.
,
Costa-Pereira
A. P.
,
Watling
D.
,
Kerr
I. M.
,
Sheer
D.
.
2007
.
P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFNgamma.
J. Cell Sci.
120
:
3262
3270
.
93
Miller
D. M.
,
Cebulla
C. M.
,
Sedmak
D. D.
.
2002
.
Human cytomegalovirus inhibition of major histocompatibility complex transcription and interferon signal transduction.
Curr. Top. Microbiol. Immunol.
269
:
153
170
.
94
Liu
W. H.
,
Liu
J. J.
,
Wu
J.
,
Zhang
L. L.
,
Liu
F.
,
Yin
L.
,
Zhang
M. M.
,
Yu
B.
.
2013
.
Novel mechanism of inhibition of dendritic cells maturation by mesenchymal stem cells via interleukin-10 and the JAK1/STAT3 signaling pathway.
PLoS One
8
:
e55487
.
95
Olszak
T.
,
Neves
J. F.
,
Dowds
C. M.
,
Baker
K.
,
Glickman
J.
,
Davidson
N. O.
,
Lin
C. S.
,
Jobin
C.
,
Brand
S.
,
Sotlar
K.
, et al
.
2014
.
Protective mucosal immunity mediated by epithelial CD1d and IL-10.
Nature
509
:
497
502
.
96
Iyer
A. K.
,
Liu
J.
,
Gallo
R. M.
,
Kaplan
M. H.
,
Brutkiewicz
R. R.
.
2015
.
STAT3 promotes CD1d-mediated lipid antigen presentation by regulating a critical gene in glycosphingolipid biosynthesis.
Immunology
146
:
444
455
.
97
Wilson
R. P.
,
Ives
M. L.
,
Rao
G.
,
Lau
A.
,
Payne
K.
,
Kobayashi
M.
,
Arkwright
P. D.
,
Peake
J.
,
Wong
M.
,
Adelstein
S.
, et al
.
2015
.
STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function.
J. Exp. Med.
212
:
855
864
.
98
Ridley
A. J.
2006
.
Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking.
Trends Cell Biol.
16
:
522
529
.
99
Riento
K.
,
Ridley
A. J.
.
2003
.
Rocks: multifunctional kinases in cell behaviour.
Nat. Rev. Mol. Cell Biol.
4
:
446
456
.
100
Bernard
O.
2007
.
Lim kinases, regulators of actin dynamics.
Int. J. Biochem. Cell Biol.
39
:
1071
1076
.
101
Gallo
R. M.
,
Khan
M. A.
,
Shi
J.
,
Kapur
R.
,
Wei
L.
,
Bailey
J. C.
,
Liu
J.
,
Brutkiewicz
R. R.
.
2012
.
Regulation of the actin cytoskeleton by Rho kinase controls antigen presentation by CD1d.
J. Immunol.
189
:
1689
1698
.
102
Torreno-Pina
J. A.
,
Manzo
C.
,
Salio
M.
,
Aichinger
M. C.
,
Oddone
A.
,
Lakadamyali
M.
,
Shepherd
D.
,
Besra
G. S.
,
Cerundolo
V.
,
Garcia-Parajo
M. F.
.
2016
.
The actin cytoskeleton modulates the activation of iNKT cells by segregating CD1d nanoclusters on antigen-presenting cells.
Proc. Natl. Acad. Sci. USA
113
:
E772
E781
.
103
Dhillon
A. S.
,
Hagan
S.
,
Rath
O.
,
Kolch
W.
.
2007
.
MAP kinase signalling pathways in cancer.
Oncogene
26
:
3279
3290
.
104
Panka
D. J.
,
Atkins
M. B.
,
Mier
J. W.
.
2006
.
Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma.
Clin. Cancer Res.
12
:
2371s
2375s
.
105
Roberts
P. J.
,
Der
C. J.
.
2007
.
Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.
Oncogene
26
:
3291
3310
.
106
Leicht
D. T.
,
Balan
V.
,
Kaplun
A.
,
Singh-Gupta
V.
,
Kaplun
L.
,
Dobson
M.
,
Tzivion
G.
.
2007
.
Raf kinases: function, regulation and role in human cancer.
Biochim. Biophys. Acta
1773
:
1196
1212
.
107
Mimura
K.
,
Shiraishi
K.
,
Mueller
A.
,
Izawa
S.
,
Kua
L. F.
,
So
J.
,
Yong
W. P.
,
Fujii
H.
,
Seliger
B.
,
Kiessling
R.
,
Kono
K.
.
2013
.
The MAPK pathway is a predominant regulator of HLA-A expression in esophageal and gastric cancer.
J. Immunol.
191
:
6261
6272
.
108
Hu-Lieskovan
S.
,
Mok
S.
,
Homet Moreno
B.
,
Tsoi
J.
,
Robert
L.
,
Goedert
L.
,
Pinheiro
E. M.
,
Koya
R. C.
,
Graeber
T. G.
,
Comin-Anduix
B.
,
Ribas
A.
.
2015
.
Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.
Sci. Transl. Med.
7
:
279ra41
.
109
Bradley
S. D.
,
Chen
Z.
,
Melendez
B.
,
Talukder
A.
,
Khalili
J. S.
,
Rodriguez-Cruz
T.
,
Liu
S.
,
Whittington
M.
,
Deng
W.
,
Li
F.
, et al
.
2015
.
BRAFV600E co-opts a conserved MHC class I internalization pathway to diminish antigen presentation and CD8+ T-cell recognition of melanoma.
Cancer Immunol. Res.
3
:
602
609
.
110
Ostrand-Rosenberg
S.
,
Sinha
P.
,
Chornoguz
O.
,
Ecker
C.
.
2012
.
Regulating the suppressors: apoptosis and inflammation govern the survival of tumor-induced myeloid-derived suppressor cells (MDSC).
Cancer Immunol. Immunother.
61
:
1319
1325
.
111
Schett
G.
,
Zwerina
J.
,
Firestein
G.
.
2008
.
The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis.
Ann. Rheum. Dis.
67
:
909
916
.
112
Medders
K. E.
,
Kaul
M.
.
2011
.
Mitogen-activated protein kinase p38 in HIV infection and associated brain injury.
J. Neuroimmune Pharmacol.
6
:
202
215
.
113
Bode
J. G.
,
Ehlting
C.
,
Häussinger
D.
.
2012
.
The macrophage response towards LPS and its control through the p38(MAPK)-STAT3 axis.
Cell. Signal.
24
:
1185
1194
.
114
Ansell
S. M.
,
Lesokhin
A. M.
,
Borrello
I.
,
Halwani
A.
,
Scott
E. C.
,
Gutierrez
M.
,
Schuster
S. J.
,
Millenson
M. M.
,
Cattry
D.
,
Freeman
G. J.
, et al
.
2015
.
PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma.
N. Engl. J. Med.
372
:
311
319
.
115
Tulunay
A.
,
Dozmorov
M. G.
,
Ture-Ozdemir
F.
,
Yilmaz
V.
,
Eksioglu-Demiralp
E.
,
Alibaz-Oner
F.
,
Ozen
G.
,
Wren
J. D.
,
Saruhan-Direskeneli
G.
,
Sawalha
A. H.
,
Direskeneli
H.
.
2015
.
Activation of the JAK/STAT pathway in Behcet’s disease.
Genes Immun.
16
:
170
175
.
116
Nieminen
J. K.
,
Niemi
M.
,
Sipponen
T.
,
Salo
H. M.
,
Klemetti
P.
,
Färkkilä
M.
,
Vakkila
J.
,
Vaarala
O.
.
2013
.
Dendritic cells from Crohn’s disease patients show aberrant STAT1 and STAT3 signaling.
PLoS One
8
:
e70738
.
117
Hedl
M.
,
Lahiri
A.
,
Ning
K.
,
Cho
J. H.
,
Abraham
C.
.
2014
.
Pattern recognition receptor signaling in human dendritic cells is enhanced by ICOS ligand and modulated by the Crohn’s disease ICOSLG risk allele.
Immunity
40
:
734
746
.
118
Savva
A.
,
Roger
T.
.
2013
.
Targeting toll-like receptors: promising therapeutic strategies for the management of sepsis-associated pathology and infectious diseases.
Front. Immunol.
4
:
387
.
119
Mifsud
E. J.
,
Tan
A. C.
,
Jackson
D. C.
.
2014
.
TLR agonists as modulators of the innate immune response and their potential as agents against infectious disease.
Front. Immunol.
5
:
79
.
120
Cervantes
J. L.
,
Hawley
K. L.
,
Benjamin
S. J.
,
Weinerman
B.
,
Luu
S. M.
,
Salazar
J. C.
.
2014
.
Phagosomal TLR signaling upon Borrelia burgdorferi infection.
Front. Cell. Infect. Microbiol.
4
:
55
.
121
Skevaki
C.
,
Pararas
M.
,
Kostelidou
K.
,
Tsakris
A.
,
Routsias
J. G.
.
2015
.
Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious diseases.
Clin. Exp. Immunol.
180
:
165
177
.
122
Song
B.
,
Zhang
Y.
,
Chen
L.
,
Zhou
T.
,
Huang
W.
,
Zhou
X.
,
Shao
L.
.
2016
.
The role of Toll-like receptors in periodontitis.
Oral Dis.
123
Marques
C. P.
,
Maor
Y.
,
de Andrade
M. S.
,
Rodrigues
V. P.
,
Benatti
B. B.
.
2016
.
Possible evidence of systemic lupus erythematosus and periodontal disease association mediated by Toll-like receptors 2 and 4.
Clin. Exp. Immunol.
183
:
187
192
.
124
Trejo-de la O
A.
,
Hernández-Sancén
P.
,
Maldonado-Bernal
C.
.
2014
.
Relevance of single-nucleotide polymorphisms in human TLR genes to infectious and inflammatory diseases and cancer.
Genes Immun.
15
:
199
209
.
125
Mohammad Hosseini
A.
,
Majidi
J.
,
Baradaran
B.
,
Yousefi
M.
.
2015
.
Toll-like receptors in the pathogenesis of autoimmune diseases.
Adv. Pharm. Bull.
5
(
Suppl. 1
):
605
614
.
126
Medvedev
A. E.
2013
.
Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer.
J. Interferon Cytokine Res.
33
:
467
484
.
127
Ve
T.
,
Gay
N. J.
,
Mansell
A.
,
Kobe
B.
,
Kellie
S.
.
2012
.
Adaptors in toll-like receptor signaling and their potential as therapeutic targets.
Curr. Drug Targets
13
:
1360
1374
.
128
Page
D. B.
,
Postow
M. A.
,
Callahan
M. K.
,
Allison
J. P.
,
Wolchok
J. D.
.
2014
.
Immune modulation in cancer with antibodies.
Annu. Rev. Med.
65
:
185
202
.
129
Sharma
P.
,
Allison
J. P.
.
2015
.
The future of immune checkpoint therapy.
Science
348
:
56
61
.

The author has no financial conflicts of interest.