INTRODUCTION — T cell recognition of antigen forms the basis of adaptive T cell immunity. Antigen is digested into peptides and bound to major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) for presentation to T cells. Recognition of self and foreign peptides by T cell receptor (TCR) complexes on immature thymocytes and mature T cells is necessary for the positive and negative selection of developing thymocytes and the functional responses of T cells. This topic briefly reviews signaling through the TCR complex, identifying the proteins involved and highlighting downstream targets of the signaling cascade.
TCR genetics, structure, and biology are covered in detail separately. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation' and "The adaptive cellular immune response: T cells and cytokines", section on 'T cell activation and functions' and "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'Overview of T cell receptor biology'.)
Reviews related to combined immunodeficiencies caused by defects in TCR complex molecules are also presented separately. (See "CD3/T cell receptor complex disorders causing immunodeficiency" and "Combined immunodeficiencies: An overview" and "ZAP-70 deficiency".)
BRIEF OVERVIEW OF THE SIGNALING CASCADE — TCR signaling in naïve T cells is initiated by TCR binding to peptide major histocompatibility complex (pMHC) complexes on the surface of antigen presenting cells (APCs). This engagement leads to a series of intracellular signaling events that culminate in the generation of a T cell response (figure 1) [1-6].
The Src-family protein tyrosine kinase Lck is first activated with resultant phosphorylation of CD3 coreceptor cytoplasmic domains, specifically at motifs known as immunoreceptor tyrosine-based activation motifs (ITAMs). These phosphorylated ITAMs on CD3-zeta serve as binding sites for the zeta chain-associated protein kinase, ZAP-70. ZAP-70 is activated by Lck-mediated phosphorylation and subsequent autophosphorylation. Activated ZAP-70 then phosphorylates a variety of linker/adapter proteins, such as linker for activation of T cells (LAT) and Src-homology 2 domain-containing 76-kDa leukocyte protein (SLP-76). Further signaling proteins are then recruited, resulting in calcium mobilization, actin cytoskeleton reorganization, and activation of Ras guanosine triphosphate hydrolases (GTPases).
Downstream from these events, there is activation of transcription factors, such as nuclear factor of activated T cells (NF-AT), activator protein 1 (AP-1), and nuclear factor kappa light-chain enhancer of activated B cells (NF-kappa-B), with resultant alterations in the pattern of T cell gene expression, proliferation, and differentiation of effector function.
EARLY SIGNAL TRANSDUCTION — The TCR is a heterodimer, with approximately 95 percent of peripheral blood T cells expressing an alpha and a beta chain. The alpha and beta chains of the TCR lack substantial cytoplasmic extensions and communicate with the interior of the cell through association with a group of single-span transmembrane proteins known as the CD3 family. CD3 gamma, delta, epsilon, and zeta form a complex with the TCR-alpha-beta receptor in a 1:1:2:2 ratio, respectively, for each TCR. In contrast to the TCR alpha and beta chains, the CD3 family members possess no known extracellular ligand-binding capacity, but have long cytoplasmic tails that serve as frameworks for intracellular signaling. The antigen-bound TCR/CD3 complex lacks intrinsic catalytic activity, and, therefore, initiation of signal transduction is critically dependent upon the activity of two protein tyrosine kinases: Lck and ZAP-70 (figure 2 and figure 1) [7-15].
Failure to express any member of the CD3 family results in some degree of immunodeficiency, often severe. CD3-gamma-deficient patients typically have near-normal T cell numbers, although with reduced TCR/CD3 complex expression, and show mild immunodeficiency. In contrast, complete CD3-epsilon, CD3-delta, and CD3-zeta deficiencies typically display a T-B+(natural killer [NK]+) severe combined immunodeficiency (SCID). These all appear to result from an early block in T cell development. Partial deficiencies in expression of individual CD3 chains have been reported, typically with less severe immunodeficiency. NK cytotoxic function is also altered in CD3-zeta deficiency. (See "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'CD3 deficiency' and "Severe combined immunodeficiency (SCID): Specific defects", section on 'CD3 complex component deficiencies'.)
Lck — Lck is a 56-kDa member of the Src-family tyrosine kinase family that is found constitutively associated with the cytoplasmic domain of the TCR coreceptors, CD4 and CD8 (figure 1). It is activated rapidly following antigen binding to the TCR. Lck activity is absolutely required for normal T cell development and function.
Lck has two critically important roles in the initiation of TCR signaling. The first is phosphorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) present in the cytoplasmic domains of the CD3 chains. These mediate interaction with other kinases (eg, CD3-epsilon ITAM binds the Src-family kinase Fyn, while ZAP-70 binds CD3-zeta) [16-22]. The second is phosphorylation of ZAP-70 on multiple residues subsequent to its recruitment to phosphorylated CD3-zeta chains, inducing activation of ZAP-70 [16,21-23]. In addition to its initiatory role in TCR signaling, Lck also has other functions further downstream in the signaling pathway (eg, phosphorylation of the Emt/Itk kinase).
Deficiency of Lck is reported to result in an immunodeficiency characterized by selective CD4 lymphopenia. Patients demonstrate the typical failure to thrive seen in SCID, opportunistic infections, and low to absent immunoglobulins. (See "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'Lck deficiency' and "Idiopathic CD4+ lymphocytopenia".)
The Lck protein is composed of a catalytic protein tyrosine kinase domain, a Src-homology 2 (SH2) domain that recognizes phosphorylated tyrosine residues in the general context TyrXXLeu, and a Src-homology 3 (SH3) domain that can bind proline rich motifs, generally with the pattern ProXProXXPro (where X equals any amino acid). Lck undergoes lipid modification during synthesis, with N-terminal myristoylation anchoring it to the inner leaflet of the T cell plasma membrane.
There are two main tyrosine phosphorylation sites on Lck itself, residues 394 and 505. Tyr394 is an autophosphorylation site on the activation loop of the Lck catalytic domain, (Tyr394 phosphorylation results in Lck activation). Phosphorylation of the activation loop causes it to be repelled from the mouth of the catalytic site, enhancing substrate access. In contrast, Tyr505 undergoes negative regulatory phosphorylation by the c-Src kinase (Csk), leading to a "closed" conformation of Lck. The phosphorylated residue is bound by the Lck SH2 domain, folding up the protein into a conformation that blocks substrate access to the active site.
The interplay between Tyr394 and Tyr505 phosphorylation in regulating Lck catalytic activity is complex. Modification of Tyr505 alone is insufficient to turn off Lck. Rather, phosphorylation of Tyr505 appears to merely shift the dynamic equilibrium between an open and closed conformation to favor more time spent in the closed state. Dephosphorylation of Tyr394 must also occur to completely downregulate Lck catalytic activity. To this end, the tyrosine phosphatase PTPN22  is believed to act in a complex with Csk to regulate Lck (and other Src-kinase family members). A variant allele of the PTPN22 phosphatase encoding an arginine to tryptophan alteration (R620W), relatively common in the White population, is linked to increased susceptibility to the development of autoimmunity [25-28]. The R620W allele of PTPN22 is a reported gain-of-function variant with increased catalytic activity that accelerates the downregulation of Lck activity subsequent to engagement of the TCR [25-30].
Furthering the regulation of early signaling events, a transmembrane adaptor protein phosphoprotein associated with glycosphingolipid microdomains (PAG/Cbp) is basally tyrosine phosphorylated in resting human T cells and subsequently bound by the SH2 domain of Csk, maintaining Csk at the plasma membrane. PAG/Cbp undergoes rapid dephosphorylation following TCR stimulation, with accompanying loss of Csk binding and recruitment to the membrane, permitting TCR signaling to proceed. Overexpression of PAG inhibits TCR-mediated responses. Cbp phosphorylation is regulated by the Src-kinase family member Fyn [31,32].
Early models of TCR signaling suggested that Lck was activated by interaction with the receptor tyrosine phosphatase CD45 following TCR recognition of antigen/major histocompatibility complex (MHC), removing negative regulatory phosphorylation from the kinase. However, subsequent findings suggest that a large percentage of thymocytes and resting T cells already contain a large pool of preactivated Lck, priming them for a rapid response. Conformational changes releasing constraints on Lck, or changes promoting Lck interaction with CD3 cytoplasmic domains, are now believed to initiate signal transduction. Studies demonstrate a close electrostatic-based interaction between the unactivated CD3-epsilon cytoplasmic domain and the inner leaflet of the plasma membrane, resulting in the insertion of key tyrosines into the lipid bilayer, potentially segregating them from Lck .
ZAP-70 — An appreciation of the role of ZAP-70 in the biology of T cells and in TCR signaling came first from the description of a human deficiency of ZAP-70. This deficiency results in an unusual combined immunodeficiency where normal CD4+ T cells counts are present in the periphery, but CD8+ T cells are absent [34,35]. ZAP-70-deficient thymi have normal architecture, but single-positive CD8+ cells are absent from the medulla  due to a block between double-negative and double-positive cells . CD4+ peripheral T cells are nonfunctional, and patients require hematopoietic stem cell replacement (ie, transplantation) to generate a functional T cell pool. (See "ZAP-70 deficiency".)
The ZAP-70 tyrosine kinase is recruited to the TCR complex following ITAM phosphorylation of the CD3-zeta chain by Lck [19,20,38-41]. ZAP-70 possesses tandem SH2 domains that bind the phosphorylated CD3-zeta ITAM motif. ITAMs are four amino acid SH2 domain binding sequences, YXX(L/V) that occur as a pair and are separated by a six to nine residue spacer region. Two SH2 domains were predicted in the ZAP-70 structure, but radiograph crystallographic analysis demonstrated that only one of these bound in the predicted manner, forming a specific pocket to enclose one of the phosphorylated tyrosine residues of CD3-zeta . The second ZAP-70 SH2 domain formed an incomplete pocket, with atypical binding of the second phosphorylated tyrosine observed .
Following binding to CD3-zeta, ZAP-70 undergoes phosphorylation at specific tyrosine residues, primarily by Lck, but also as the result of transautophosphorylation [38,43-46]. Much of the increase in ZAP-70 kinase activity following TCR stimulation is associated with the specific phosphorylation of Tyr493 in the activation loop of the ZAP-70 catalytic domain [43-46], although the act of binding CD3-zeta also causes conformational changes that increase activity. Binding to the phosphorylated CD3-zeta ITAM may further serve to fully expose Lck regulatory phosphorylation sites.
Phosphorylation of Tyr315 and Tyr319 within ZAP-70 also promotes TCR signal transduction by functioning as binding sites for downstream molecules: Tyr315 for the Vav guanine nucleotide exchange factor [47-49] and Tyr 319 for phospholipase Cγ 1 [47,50-52], presumably directing access for their phosphorylation by the ZAP-70 kinase domain.
ZAP-70 enzymatic activity is also negatively regulated by phosphorylation at Tyr492 [43,44,53]. Furthermore, phosphorylation of Tyr292 has been shown to downregulate ZAP-70 function by serving as a binding site for the ubiquitin ligase, Cbl. The E3-ubiquitin ligase Cbl modifies ZAP-70 through ubiquitylation of lysine residues, targeting it for proteasomal degradation [54,55]. Cbl negatively regulates the activation of a number of TCR signal transducing proteins by inducing their degradation. ZAP-70 activity also appears to be downregulated as a result of the removal of activating tyrosine phosphorylation by cytoplasmic tyrosine phosphatases, including PTPN22 .
DISTAL CASCADE — Engagement of the TCR/CD3 complex by peptide major histocompatibility complex (pMHC) and subsequent activation of Lck and ZAP-70 kinases trigger a signaling cascade within the cell. This cascade culminates in the activation of pathways inducing transcription factor activity, with subsequent proliferation, differentiation, and cytokine secretion (figure 1).
The three major enzymatic pathways activated by TCR ligation are the mitogen-activated protein kinases (MAPK), the Rho family guanosine triphosphate hydrolases (GTPases), and phosphoinositol-regulated pathways. These pathways send signals into the nucleus via transcription factors, such as activator protein 1 (AP-1, dimer of Jun and Fos) and the nuclear factor of activated T cells (NF-AT).
The downstream interactions result in signal amplification and culminate in the transcription of genes required for T cell activation and initiation of T cell-specific responses, such as CD69 upregulation and interleukin-2 (IL-2) secretion in mature naïve T cells. The molecules and processes involved in the subsequent downstream cascade continue to be identified.
ZAP-70-mediated tyrosine phosphorylation events are required for the mobilization of intracellular free calcium ([Ca2+]i)  and activation of the Ras/MAPK and phosphatidylinositol-3 (PI-3) kinase pathways [56-63]. Specific substrates for ZAP-70 include the adaptor proteins linker for activation of T cells (LAT) and Src-homology 2 (SH2) domain-containing 76-kDa leukocyte protein (SLP-76) [9-13,51,56-61,64]. Additional molecules that are recruited to the TCR via interactions with ZAP-70 or ZAP-70 substrates include Cbl, Vav, Grb-2, Sos, Gads, Itk, Ras-GTPase activating protein (GAP), and the p85 subunit of PI-3 kinase [9-13,38,48,49,56-62,65].
LAT — ZAP-70 efficiently phosphorylates the integral membrane adaptor protein LAT. Phosphorylated LAT acts as a scaffold, promoting the interaction of a number of signal transducing proteins including the adaptor Grb2-related adaptor protein-2 (GRAP2/Gads), SLP-76, IL-2 inducible T cell kinase (ITK), Grb2, p85 PI-3 kinase and phospholipase C gamma 1 (PLC-gamma-1). T cell development does not proceed beyond the earliest stages in the absence of LAT [66,67]. Palmitoylation during synthesis sequesters LAT into the lipid raft compartment of the plasma membrane.
Grb2 binding to LAT serves to recruit Son of Sevenless (SOS), a guanine nucleotide exchange factor for the small GTPase Ras, leading to the activation of Ras and the MAPK cascade, with important roles in cellular activation and regulation of the cell cycle. The Ras guanyl nucleotide-releasing protein (RasGRP) is also recruited to the plasma membrane upon generation of diacylglycerol (DAG) and activated by protein kinase C (PKC)-theta-mediated serine phosphorylation.
SLP-76 is also an adaptor protein, recruiting ITK, Gads, Vav, and Nck to the LAT signalosome. In association with Vav, SLP-76 and LAT lead to activation of the Rho family of small GTPases, cdc42 and Rac1. These function in cytoskeletal reorganization. SLP-76 and LAT also link the TCR to activation of PI-3 kinase. PI3-kinase modifies membrane phosphatidylinositol (PtdIns) lipids, phosphorylating the 3' position hydroxyl group of the inositol ring.
Lipid and lipid derived messengers — Generation of 3'-phosphorylated-inositol lipids in the plasma membrane can create binding sites for signaling molecules possessing a PtdIns-binding pleckstrin homology (PH) domain, including the cytoplasmic expressed in mast and T cells/IL-2-inducible T cell tyrosine kinase (Emt/Itk) that is recruited to the membrane following TCR activation. Emt/Itk also binds the membrane adapter LAT via its SH2 domain, after phosphorylation of LAT by ZAP-70. Emt/Itk is subsequently activated via Lck-mediated tyrosine phosphorylation. Emt/Itk-deficient mice display compromised PLC-gamma-1 phosphorylation and reduced extracellular calcium flux in response to TCR stimulation [68-72].
PI3-kinase activity is also responsible for PH domain-dependent recruitment of PLC-gamma-1 in response to TCR engagement through the generation of phosphatidylinositol(3,4,5)trisphosphate in the plasma membrane. SLP-76 and LAT also link to the PLC-gamma-1 pathway. PH domain-mediated docking to the plasma membrane also recruits 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and its substrate Akt (also called protein kinase B,PKB), activating this survival promoting pathway [73,74].
PLC-gamma-1 cleaves phosphatidylinositol(4,5)bisphosphate into DAG and inositol triphosphate (IP3). Membrane-bound DAG activates members of the PKC family, in particular PKC-theta, which plays important roles in activation of Ras and the transcription factor nuclear factor kappa light-chain enhancer of activated B cells (NF-kappa-B). In unstimulated cells, NF-kappa-B is sequestered to the cytoplasm by interaction with the inhibitor of kappa-B (I-kappa-B). NF-kappa-B activation requires I-kappa-B degradation. In a signal cascade, DAG-activated PKC-theta phosphorylates the I-kappa-B kinase IKK, which in turn phosphorylates I-kappa-B, causing its ubiquitination and subsequent degradation, freeing NF-kappa-B to translocate into the nucleus. DAG also recruits Ras guanyl nucleotide-releasing protein (RasGRP) to the membrane where the guanine release factor undergoes PKC-theta-mediated activating phosphorylation and helps activate the Ras signaling pathway.
Soluble IP3 mobilizes calcium from intracellular storage sites by binding to IP3 receptors on the surface of the endoplasmic reticulum (ER).
Calcium — Sustained elevation of cytosolic levels of free calcium (Ca2+) plays a critical role in promoting TCR signaling. Several hours of Ca2+ influx are required to complete T cell activation. In particular, elevated Ca2+ maintains prolonged nuclear accumulation of NF-AT by activating the phosphatase calcineurin, which dephosphorylates the cytoplasmic form of the transcription factor NF-AT, allowing it to enter the nucleus and initiate transcription.
Store-operated Ca2+ entry is used by many types of cells, including lymphocytes, to increase intracellular Ca2+ concentrations to initiate signal transduction . Activation of the TCR results in an IP3-dependent release of Ca2+ ions from ER Ca2+ stores. Depletion of Ca2+ from this internal store subsequently leads to the opening of plasma membrane ion channels allowing an influx of external Ca2+.
Stromal interaction molecule 1 (STIM1) expressed in the ER senses ER calcium ion levels and is responsible for triggering Ca2+ release-activated Ca2+ (CRAC) channels. Patients with STIM1 mutations abrogating STIM1 expression (and subsequently Ca2+ influx) present with many immune defects, including immunodeficiency, hepatosplenomegaly, autoimmune hemolytic anemia, and thrombocytopenia. Studies of STIM1-deficient mice suggest that STIM1-dependent store-operated Ca2+ entry is critical for homeostatic T cell proliferation but less important for T cell differentiation or effector function . (See "Syndromic immunodeficiencies".)
Mutations in ORAI1, the gene encoding the pore-forming subunit of the CRAC channel, abrogate the store-operated entry of Ca2+ into cells and also impair lymphocyte activation. In humans, ORAI1 deficiency presents with normal lymphocyte counts and serum immunoglobulin levels but is characterized by recurrent infections, impaired T cell activation and proliferative responses, and decreased production of cytokines. (See "Syndromic immunodeficiencies".)
Actin — Activation of the Vav/Rho family signaling pathway leading to rearrangement of the actin cytoskeleton plays a critical role in sustaining the T cell signaling response. TCR activation typically occurs upon encounter with antigen-loaded MHC on antigen presenting cells (APCs). At this point, the T cell undergoes a transition from a highly motile cell in an APC scanning mode to one favoring relatively stable interactions. TCR engagement leads to the rapid formation of filamentous actin, required for polarization or reorientation of the T cell towards the stimulating cell .
Effective T cell response appears dependent upon the formation of a highly spatially ordered interface between the T cell and APC referred to as the immunologic synapse (IS) or supramolecular activation cluster (SMAC) [78-80]. This structure is composed of concentric rings each containing specific receptors and signaling proteins. As examples, the TCR/CD3 complex and associated signaling proteins cluster into a "central supramolecular activation cluster" (c-SMAC), while lymphocyte function-associated antigen 1 (LFA-1) integrin is found in a peripheral SMAC (p-SMAC) that forms a ring of adhesion between the cells. The maintenance of an intact IS for many hours appears to be required for the effective activation of the T cell, although the identity of the particular APC (eg, dendritic cell, macrophage, B cell) may significantly affect requirements. The stable synapse may also provide a focal point for focused secretion and endocytosis. (See "Antigen-presenting cells".)
TCR signaling-induced rearrangement of the actin cytoskeleton plays a critical role in decreasing T cell motility, in the molecular segregation of the T cell surface receptors, and in spatial organization of intracellular signaling components. Even prior to the formation of the mature IS, activated TCR/CD3 complexes form microclusters that localize into the c-SMAC in a process dependent upon actin polymerization. Thus, early signaling events prepare the platform for sustained distal signaling and T cell responses. Evidence suggests that the c-SMAC have an active TCR signaling zone and a TCR downregulating zone that uses ubiquitination machinery. PKC-theta and Wiskott–Aldrich syndrome protein (WASp) activity critically regulate synapse stability. Immunologic synapses are hyperstable in PKC-theta-deficient T cells, while they are unstable in WASp-deficient cells .
Wiskott–Aldrich syndrome, or WASp deficiency, is an X-linked immunodeficiency in humans characterized by increased susceptibility to infections, eczema, thrombocytopenia, and decreased antibody production. Patients also display autoimmune disease and an increased incidence of malignancy, although the type of WAS mutation correlates significantly with the degree of disease severity. WASp-deficient T cells show impaired proliferation and actin rearrangement. (See "Wiskott-Aldrich syndrome".)
TCR-mediated activation of T cell adhesion molecules such as LFA-1 is also critical to IS formation. The mechanism by which inside-out signaling to activate LFA-1 operates is unclear but involves activation of the Rac GTP exchange factor (GEF) Vav and the Rap1 GEF, C3G. Rap1 may be recruited to the plasma membrane by the adhesion and degranulation-promoting adaptor protein/Src kinase-associated phosphoprotein of 55 kDa (ADAP/SKAP55) adapter protein complex.
For a more detailed review of TCR signaling kinetics at the synapse, see .
TCR SIGNALING IN T CELL ONTOGENY — The TCR/CD3 complex is not only absolutely required for the proper function of mature T cells, but also plays a significant role in T cell ontogeny (figure 3). (See "Normal B and T lymphocyte development".)
Early in the differentiation of the thymocyte, genomic DNA encoding one of the TCR-beta chains undergoes physical rearrangement to create a functional gene in a process known as V(D)J recombination (somatic recombination of the variable, diverse, and joining gene segments). This is dependent upon recombinase-activating genes 1 and 2 (RAG1 and RAG2) [1,2]. Failure to correctly rearrange the TCR-beta locus as a result of defective RAG enzyme activity results in severe combined immunodeficiency (SCID) that often presents as Omenn syndrome . (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis".)
The differentiating thymocyte identifies functional rearrangement of the TCR-beta gene by its ability to signal. The rearranged TCR-beta chain associates with an invariant pre-TCR-alpha (pT-alpha) chain to form an active pre-TCR complex with CD3 chains that is hypothesized to signal in a nonligand-dependent manner. This may be due to a high potential for self-multimerization, conferring autonomous signaling [84,85]. Signaling through the pre-TCR complex involves many of the same proteins critical to mature TCR signaling including ZAP-70, linker for activation of T cells (LAT), Lck, Fyn, and phospholipase C gamma 1 (PLC-gamma-1), although their relative importance may vary [86-89]. Pre-TCR signals promote thymocyte survival and proliferation, expression of CD4 and CD8 coreceptors, rearrangement of TCR-alpha, and also induce a process known as allelic exclusion, whereby rearrangement of the second TCR-beta allele is prevented. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.)
T cell precursors in the thymus with correctly rearranged TCR alpha and beta chains undergo positive and negative selection processes before they mature into CD4+ or CD8+ T cells . The fate of these cells is determined in large part by the interaction of the TCR/CD3 complex with self-antigens presented by thymic epithelial cells. Strong interaction and, as a result, a prolonged/high level of TCR signaling in the thymocyte indicates that there is the potential for autoreactivity, and these cells are deleted (negative selection). A weak to moderate interaction between the thymocyte and self-antigen presenting epithelial cells allows the cells to mature (positive selection). Levels of phosphorylated (activated) ZAP-70 and mitogen-activated protein kinase (MAPK) activation have been identified as critical signaling events linked to the selection process. (See "Normal B and T lymphocyte development".)
CD3 or TCR chain deficiency may prevent the proper interaction of the precursors with the thymic epithelium, therefore eliminating the selection process. (See "CD3/T cell receptor complex disorders causing immunodeficiency".)
A failure to negatively select or delete self-recognizing cells because of failure to express self-antigens in the thymus results in multisystem autoimmunity, as observed in autoimmune regulator (AIRE) transcription factor deficiency that causes autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) [91,92]. (See "Chronic mucocutaneous candidiasis", section on 'Autoimmune regulator deficiency'.)
Syk — Syk is a 72-kDa molecule with significant homology to ZAP-70. Expressed predominantly in B cells and myeloid cells, Syk is also found in thymocytes and at low levels in some mature T cells . It is critical to B cell receptor (BCR) signaling and functions in B cells in a manner fairly analogous to ZAP-70 in T cells. In murine thymocytes, Syk plays a role in TCR signaling. Syk binds phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) and can be activated by pre-TCR and TCR stimulation [8,16,94]. Analysis of mice deficient in both Syk and ZAP-70 demonstrated that Syk is critical to early pre-TCR signaling in CD4- CD8- double-negative thymocytes and may induce ZAP-70 expression required for subsequent thymocyte selection [86-88,95-97]. (See "ZAP-70 deficiency".)
Themis — Thymocyte-expressed molecule involved in selection (Themis) is a protein of unknown function that is highly conserved among vertebrates. It is highly expressed in thymocytes between the pre-T cell antigen receptor and positive-selection checkpoints, with lower expression in mature T cells. Themis-deficient mice have few thymocytes, with a defect in positive selection, resulting in fewer mature thymocytes. Themis undergoes rapid tyrosine phosphorylation that is dependent upon LAT and Src-homology 2 domain-containing 76-kDa leukocyte protein (SLP-76) and interacts with LAT, PLC-gamma-1, Grb2 and inducible T cell kinase (ITK). The precise role of Themis in TCR signaling is still unclear, but T cells lacking THEMIS gene expression demonstrate reduced interleukin-2 (IL-2) expression following TCR stimulation as a result of reduced extracellular signal-regulated kinases (ERK) and nuclear factor of activated T cells (NF-AT)/activator protein 1 (AP-1) signaling. Evidence suggests that Themis is required for optimal calcium mobilization and MAPK activation [84,98,99].
NATURAL KILLER CELL SIGNALING — As in T cells, some of the activating receptors expressed by natural killer (NK) cells possess immunoreceptor tyrosine-based activation motifs (ITAMs) that, when phosphorylated, can recruit ZAP-70 or Syk kinases to the plasma membrane for initiation of downstream signaling events [85,100,101]. ZAP-70 function is not absolutely required for human NK cell differentiation or cytotoxicity in vivo, unlike T cell ontogeny [85,100,102]. However, Syk may be critical for NK function, at least in humans [100,101]. (See "ZAP-70 deficiency", section on 'Pathogenesis' and "NK cell deficiency syndromes: Clinical manifestations and diagnosis" and "NK cell deficiency syndromes: Treatment".)
CORECEPTORS — Although not discussed above, the coligation or activation of TCR coreceptors such as CD4, CD8, CD28, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and other receptors, such as lymphocyte function-associated antigen 1 (LFA-1), can dramatically affect the final outcome of the TCR signaling cascade through the ability of these receptors to reinforce or inhibit the activation of signal transducing proteins in specific pathways . (See "Normal B and T lymphocyte development" and "The adaptive cellular immune response: T cells and cytokines".)
●Engagement of the T cell receptor (TCR) with peptide bound to the major histocompatability complex (MHC) expressed on antigen presenting cells (APCs) leads to a series of events that culminate in the generation of T cell responses (figure 1). (See 'Introduction' above and 'Brief overview of the signaling cascade' above.)
●Activation of early signaling molecules triggers a distal cascade in the cell, culminating in the activation of pathways that induce transcription factors, with subsequent proliferation, differentiation, and cytokine secretion responses. Three main pathways activated by T cell ligation are the mitogen-activated protein kinases (MAPK), the Rho family guanosine triphosphate hydrolases (GTPases), and phosphoinositol-regulated pathways. (See 'Distal cascade' above.)
●The TCR/CD3 complex is mandatory for the proper function of mature T cells and also plays a significant role in T cell ontogeny (figure 3). The processes involved in CD4 versus CD8 selection during T cell ontogeny require signal transduction through the pre-TCR and TCR of the differentiating thymocyte. The signaling events mediated by the pre-TCR and TCR on thymocytes are similar to those responsible for the activation of mature T cells. (See 'TCR signaling in T cell ontogeny' above and "Normal B and T lymphocyte development".)
●ZAP-70 function is not absolutely required for natural killer (NK) cell differentiation or cytotoxicity. However, Syk may be critical for NK function. (See 'Natural killer cell signaling' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
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