key: cord-0923229-x4zvm6px
authors: Gangopadhyay, Kaustav; Roy, Swarnendu; Sen Gupta, Soumee; Chandradasan, Athira C.; Chowdhury, Subhankar; Das, Rahul
title: Regulating the discriminatory response to antigen by T-cell receptor
date: 2022-03-23
journal: Biosci Rep
DOI: 10.1042/bsr20212012
sha: 50f6deff6ceff13abb3b87c96b868bf45c781b04
doc_id: 923229
cord_uid: x4zvm6px

The cell-mediated immune response constitutes a robust host defense mechanism to eliminate pathogens and oncogenic cells. T cells play a central role in such a defense mechanism and creating memories to prevent any potential infection. T cell recognizes foreign antigen by its surface receptors when presented through antigen-presenting cells (APCs) and calibrates its cellular response by a network of intracellular signaling events. Activation of T-cell receptor (TCR) leads to changes in gene expression and metabolic networks regulating cell development, proliferation, and migration. TCR does not possess any catalytic activity, and the signaling initiates with the colocalization of several enzymes and scaffold proteins. Deregulation of T cell signaling is often linked to autoimmune disorders like severe combined immunodeficiency (SCID), rheumatoid arthritis, and multiple sclerosis. The TCR remarkably distinguishes the minor difference between self and non-self antigen through a kinetic proofreading mechanism. The output of TCR signaling is determined by the half-life of the receptor antigen complex and the time taken to recruit and activate the downstream enzymes. A longer half-life of a non-self antigen receptor complex could initiate downstream signaling by activating associated enzymes. Whereas, the short-lived, self-peptide receptor complex disassembles before the downstream enzymes are activated. Activation of TCR rewires the cellular metabolic response to aerobic glycolysis from oxidative phosphorylation. How does the early event in the TCR signaling cross-talk with the cellular metabolism is an open question. In this review, we have discussed the recent developments in understanding the regulation of TCR signaling, and then we reviewed the emerging role of metabolism in regulating T cell function.

The cell-mediated immunity is carried out by a repertoire of clonally diverse T lymphocytes that display unique antigen-binding receptors on the cell surface called T-cell receptors (TCRs). The TCR binds to the foreign antigen, presented as peptide-major histocompatibility complex (pMHC) through antigen-presenting cells (APCs) with remarkable selectivity and sensitivity ( Figure 1 ) [1] [2] [3] [4] . The formation of the TCR-pMHC complex initiates a cascade of downstream signaling that remodels cell metabolism and gene expression causing T cells to exit quiescence [5] [6] [7] [8] . TCR signaling is also essential for T-cell development and maturation [9] [10] [11] . T lymphocytes migrate to the thymus gland from bone marrow to develop into mature T cells [11] [12] [13] . T cells undergo a series of selection processes in the thymus that train them to distinguish between self and foreign antigen. In the first selection step, T cells undergo positive selection to create a repertoire of self-MHC-restricted T lymphocytes [14] [15] [16] . In the subsequent steps, T cells that react too strongly with self-MHC or self-peptides are eliminated by the process of negative selection producing self-tolerant T cells [17] [18] [19] [20] [21] [22] [23] . The key proteins known to regulate kinetic proofreading in the early TCR signaling are highlighted. Following the binding of pMHC to the TCR complex, Lck is activated and brought into proximity of the CD3 complex. Lck then phosphorylates the ITAMs in the CD3 chains (phosphorylation depicted as red dots). ZAP-70 is recruited to the TCR complex through the tSH2 domain and doubly phosphorylated ITAM interaction. Activated ZAP-70 phosphorylate scaffold protein LAT connects the TCR to indicated downstream cellular response through multiple signaling pathways. Abbreviations: ITAM, immunoreceptor tyrosine-based activation motif; LAT, linker for activation of T cells; Lck, lymphocyte-specific protein tyrosine kinase; tSH2, two SH2 domains; ZAP-70, zeta chain-associated protein tyrosine kinase.

Central to the TCR response lies a delicate balance that helps discriminate between 'self' versus 'non-self' peptides while maintaining high sensitivity against small amounts of non-self antigen (agonist). TCR does not possess intrinsic catalytic activity; it responds to antigen binding by recruiting several enzymes and adaptor proteins following a mechanism that may have evolved 500 million years ago in jawed fish [24] [25] [26] [27] [28] [29] [30] . Early TCR signaling begins with assembling coreceptors at the TCR [31] [32] [33] [34] , phosphorylation of key non-receptor tyrosine kinases [35, 36] , and adaptor proteins [37] [38] [39] that helps propagate the signaling downstream ( Figure 1) . A kinetic proofreading mechanism was proposed to explain how the lifetime of TCR-pMHC complex and subsequent delayed recruitment and activation of enzymes fine-tune the TCR downstream signaling [40] [41] [42] . In this review, we focus on the regulation of early TCR signaling. We have discussed recently published experimental evidence that explained how such a proofreading mechanism works in T cells. In recent years, it has become evident that remodeling of glucose metabolism is critical in determining the output of TCR signaling. In the final section, we discuss the emerging role of metabolic cues in regulating T-cell signaling.

TCR is a complex of integral membrane proteins comprising α and β chains, and the CD3 chains (comprising γ, δ, ε, and ζ) that together provide an extracellular ligand-binding domain and intracellular segment for recruiting enzymes and adaptor proteins ( Figure 1) [7, 8, [43] [44] [45] [46] [47] . The extracellular domain of TCR interacts with the pMHC, initiating the signal transduction circuitry by recruiting coreceptors like CD4/CD8. The early downstream signaling begins with the recruitment and activation of two non-receptor tyrosine kinases to the TCR. First, a lymphocyte-specific protein tyrosine kinase (Lck) associated with the CD4/CD8 is recruited to the TCR complex [36, 48, 49] , which in turn phosphorylates the cytosolic segment of the CD3 (γ, ε, δ, and ζ) chain. [50] [51] [52] [53] [54] [55] . The phosphorylated CD3 chains serve as a docking site for the second non-receptor tyrosine kinase named zeta chain-associated protein tyrosine kinase (ZAP-70) [56] [57] [58] [59] . The discriminative ability of TCR relies on two different events, the affinity of the antigenic peptide for the extracellular receptor [60] and the intracellular balance between downstream kinases and phosphatases, creating a feedback regulation [61] [62] [63] [64] [65] . Activation of Lck serves a dual role; it creates the docking site for the ZAP-70 recruitment to the membrane and fully activates ZAP-70 by phosphorylating critical tyrosine residues on the kinase domain [66] [67] [68] [69] [70] . Specific phosphatases, CD45, and SHP1 [36, [71] [72] [73] [74] , control activation of Lck [36, 75, 76] , which in turn regulate the recruitment of ZAP-70 to TCR. The ZAP-70 activation is central for the propagation of TCR signaling downstream ( Figure 1 ). Together, the intricate circuitry between downstream signaling modules in the early stage of TCR signaling constitutes a proofreading mechanism making TCR sensitive to minor perturbation of antigen peptide sequence [41, 77] . Next the activated ZAP-70 propagates the signal downstream by phosphorylating a scaffold protein linker for activation of T cells (LAT) [37] [38] [39] . LAT is then recruited to the signalosome where several tyrosine residues are phosphorylated by ZAP-70. An electrostatic selection mechanism filters LAT from being non-specifically phosphorylated by Lck [78, 79] . Phosphorylated LAT connects the TCR signaling to cellular processes regulating cell migration, differentiation, and proliferation by recruiting enzymes and adaptor proteins to the signalosome ( Figure  1 ) [80] [81] [82] [83] . LAT function as a scaffold to bind adaptor proteins and enzymes like SH2 domain containing leukocyte protein of 76 kDa (SLP-76), growth factor receptor-bound protein 2 (Grb2), and phospholipase C-γ1 (PLC-γ1) connecting TCR response to the MAP kinase pathway and Ca 2+ signaling ( Figure 1 ). [84, 85] Activated ZAP-70 also regulates T-cell migration through SLP-76 phosphorylation that connects TCR signaling to Vav1 (Figure 1 ) [86] [87] [88] .

Early TCR signaling is regulated by kinetic proofreading mechanism T cells are sensitive to a very low abundance of agonist present in a large amount of self-peptide mixture. Experimentally, 60-200 molecules of the specific pMHC are sufficient for generating T-cell response [89, 90] . T cells do not rely on TCR-dependent basal signaling for survival in a ligand-free state [91] [92] [93] . Deletion of TCR does not affect the T-cell survival suggesting the TCR signaling is not indispensable for cell survival in resting state. However, TCR deletion or loss of TCR affects T-cell development and maintenance [94, 95] . These observations suggest that the general state of TCR is an OFF state. TCR could distinguish between an agonist and a partial agonist despite the marginal difference in the binding affinity [96] [97] [98] [99] [100] . The inability of the partial agonist to activate TCR downstream signaling suggests a prevalence of proofreading mechanisms that help calibrate TCR response to an agonist [101, 102] .

Two theories explaining how a proofreading mechanism may regulate T-cell response to antigen binding were proposed in the mid-nineties [40, 103, 104] . Lanzavecchia and colleagues proposed a serial triggering model suggesting that the amplification of TCR activation depends on multiple binding of the same ligand to different TCRs [103] . According to this model, a sustained TCR signaling may be generated by serially triggering large number of receptors with a limited set of pMHC molecules. For such a model to work, the ligand needs fast off rates to serially bind large number of receptors. Several computational models and experimental studies have supported the serial triggering model [105] [106] [107] [108] [109] [110] [111] . However, a direct evidence supporting serial triggering model is lacking and none of the data explained the optimal half-life of pMHC-TCR complex required to initiate an effective downstream response. Recent studies with traction force microscopy instead suggest that TCRs mechanically sense the strength of pMHC binding, and digitally activate the downstream signaling [112] [113] [114] [115] [116] .

McKeithan, in the same year as Lanzavecchia and colleagues [103] , suggested an alternate kinetic proofreading model explaining TCR response on binding agonist or a partial agonist [40] . According to the kinetic proofreading model, time delays between pMHC binding to TCR and subsequent recruitment and activation of each downstream enzyme were considered. A balance between pMHC-TCR complex formation and the delayed response of downstream signaling modules determines the TCR selectivity and sensitivity. The non-specific interaction between self-antigen (or a partial agonist) and TCR are short-lived. Hence, they do not signal because the pMHC-TCR complex disintegrates before the downstream enzymes are recruited and activated [41, 77, 117] . Recent optogenetic approaches using chimeric ligand suggested that the half-life of optoligand and TCR complex is the rate-limiting step during the formation of the initial signalosome [41, 77, 117] . The ligand:receptor half-life determines the ZAP-70-dependent diacylglycerol (DAG) accumulation, an important signaling event that connects TCR to intracellular Ca 2+ release ( Figure 1 ) [77, 117] . The interaction between foreign antigen and TCR is long-lived and finds enough time to signal by activating the kinases. Several research groups have independently studied the kinetic proofreading by TCR signaling in recent years [41, 84, [117] [118] [119] [120] . The binding of TCR and pMHC acts as a driving force for the colocalization of coreceptor, bringing Lck to the close vicinity of the cytosolic domain of TCR, facilitating phosphorylation of the CD3 chains, and subsequent recruitment of other enzymes and scaffolds (Figures 1 and  2 ). In the following section, we discussed how such an intricate network of kinase activation is regulated during T-cell response.

Lck is an Src family kinase essential for the phosphorylation of the cytosolic domain of the CD3 chain in the TCR [121, 122] . The localization of coreceptors CD4/CD8 along with Lck at the signalosome marks the activation of the first tyrosine kinase. The activated Lck phosphorylates the tyrosine residues on the immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3 chains [121, 122] . The recruitment of Lck and subsequent phosphorylation of the ITAMs contribute to the temporal lag observed in the initiation of signaling cascade [123] [124] [125] .

The secondary structure of Lck comprises an N-terminal regulatory module made up of SH4 domain, a unique domain (UD), SH3 and SH2 domain, connected to a kinase domain followed by a short C-terminal tail [126] [127] [128] [129] [130] . The autoinhibitory state of the kinase domain is stabilized by the close conformation of SH3, SH2, and kinase domain [36, 131] . The autoinhibited structure is locked in the closed conformation by docking the phosphotyrosine residue (Y505) in the C-terminal tail on the SH2 domain [130] . The Y505 is phosphorylated by C-terminal Src kinase (Csk) [132] [133] [134] . Myristylation of Ser 6 or palmitoylation of Gly 2 in the SH4 domain is essential for membrane recruitment of Lck and subsequently releasing the autoinhibition of the kinase domain. The kinase domain inhibition is released by dephosphorylating Y505 followed by autophosphorylation of Y394 in the activation loop ( Figure 2 ) [135] [136] [137] [138] [139] [140] . Membrane-associated phosphatase CD45 helps stabilize the active conformation by dephosphorylating Y505, breaking the lock between Y505 and SH2 domain [71, 141] . A delicate balance of phosphorylation and dephosphorylation regulates Lck activity. Studies using phosphomimetic mutant of Lck suggest that residue Y192 in the SH2 domain is essential in determining the equilibrium between an active and inactive conformation [131, 142] . Phosphorylation of Y192 prevents Lck interaction with the CD45, thus altering the enzymatic activity of Lck and shifting the equilibrium toward the closed-autoinhibited state [143] .

Apart from phosphorylation of Y192, Lck is also down-regulated by the phosphorylation of S59 in the UD domain [141, 144] . S59 is phosphorylated by extracellular signal-regulated kinases (Erk1/2) [145] and dephosphorylated by calcineurin [146] , creating a feedback mechanism [141] . A mutational study suggested that S59 plays a pivotal role in recruiting phosphatase SHP1, which inactivates Lck by dephosphorylating Y394 in the activation loop [147] . Conversely, studies using knock-in mutant (S59A) mice suggest a limiting role of SHP-1 interaction in favoring autoinhibited conformation of Lck during thymocyte maturation (i.e. DN to DP stage). Rather a trimeric complex between THEMIS:GRB2:SHP-1 negatively regulates Lck activation [148] .

A large intracellular concentration of Lck could phosphorylate the CD3 chain in the basal state, which may initiate TCR signaling even without binding to pMHC. The basal activity of Lck is regulated by a coordinated function of non-receptor tyrosine kinase Csk and the phosphatases (CD45 and SHP-1) [147, 149] . With such a large number of inhibitory steps, how does Lck initiate the signaling? The N-terminal region of Lck plays a major role in regulating Lck activation at the membrane. The N-terminal SH4 domain of Lck interacts with the Zinc-clasp motif located in the cytosolic tail of the coreceptor CD4/CD8, clustering Lck at along with CD45, an essential step for Lck-dependent ITAM phosphorylation [131, [150] [151] [152] [153] [154] . Kinetic segregation of Lck:CD4/CD8 complex from the CD45 and Csk may result in a high concentration of active Lck accumulation at the TCR complex [131, [155] [156] [157] [158] . Recent studies suggest that antigen-bound TCR scans for several CD4/CD8 coreceptors and finally binds with CD4/CD8 coreceptors in complex with Lck [159] . The basic residues in the CD3ε chains serve as a docking site for Lck, leading to the phosphorylation of the ITAMs [160] . The clustering of Lck to the TCR may represent an additional proofreading step, most likely following a spatial proofreading mechanism [161] . Under the basal state, the Lck is spatially arranged far from the Activated T-Cell TCR in a low substrate-concentrated region. Upon TCR activation, Lck diffuse to the high substrate concentration region contributing to additional delay in activating TCR response [161] . Under the basal condition, the residual activity of Lck could partially phosphorylate ITAMs, but is not enough for activation of ZAP-70. Complete phosphorylation of the ITAMs are required for TCR engagement, which depends on the half-life of the TCR-pMHC complex [110, 162] . The phosphorylation step acts as a threshold for the activation of T-cell signaling. In the basal state, the tyrosine residues in the cytosolic domain of the CD3 chain are embedded in the lipid bilayer, making them inaccessible for phosphorylation by Lck [163] [164] [165] . The binding of pMHC to the TCR reorients the cytosolic domain of the CD3 chain dislodging the tyrosine residues from the membrane allowing the UD of Lck to interact.

ZAP-70 is indispensable for propagating downstream TCR signaling. ZAP-70 is a Syk family kinase translated as a single polypeptide chain containing an N-terminal regulatory module connected through a flexible linker, interdomain-B, to the C-terminal catalytic module. The regulatory module comprises tandem repeats of two SH2 (tSH2) domains, N-SH2 and C-SH2, interconnected by a helical linker called interdomain-A [69, 70, [166] [167] [168] [169] . The kinase domain adopts Cdk/Src-like inactive conformation in the autoinhibited state, stabilized by a closed conformation of kinase domain, interdomain-B, and tSH2 domain sandwich [166, 170] . In the autoinhibited state, the SH2 domains are separated in an L-shaped conformation, making them incompatible with the binding doubly phosphorylated ITAM. The ZAP-70 is activated in two steps. In the first step, the autoinhibition of the kinase is partially released when the tSH2 domains bind allosterically to the phosphorylated tyrosines in the ITAM (Figure 2 ) [171] . Structural analysis suggests that the holo-tSH2 domain rearranges to a Y-shaped closed conformation exposing the Y315 and Y319 in the interdomain B to be phosphorylated [166, 169, [172] [173] [174] . The activated structure of ZAP-70 is stabilized by the phosphorylation of Y315 and Y319 in interdomain B, and tyrosine residue in the activation loop by Lck [169, 172, 173, [175] [176] [177] [178] .

Steady-state ligand-binding experiments suggest that the tSH2 domain binds to the doubly phosphorylated ITAM peptides in a biphasic manner [179] . In the first step, the C-SH2 domain binds uncooperatively to the N-terminal tyrosine phosphate with low nanomolar affinity, subsequently facilitating the formation of the N-SH2 phosphate-binding pocket enabling second phosphotyrosine to bind with micromolar affinity leading to remodeling of C-SH2-binding site. Fluorescence recovery after photobleaching (FRAP) study suggests that the recruitment of ZAP-70 follows a biphasic pattern in cells [180, 181] . The functional significance of such two-step ligand binding is still not completely understood. Comparison of the apo-and holo-structure of the tSH2 domain revealed that the N-SH2-binding pocket formed at the interface of the tSH2 domains [169, 174, 179, 182] . A non-covalent network of amino acids residues allosterically couples the tSH2 domains during ligand binding. Mutation in the allosteric network residues, including W165C that cause rheumatoid arthritis-like symptoms in mice [183] , uncouples the ligand-binding from ZAP-70 activation [179] . Thus, it is speculated that the ITAM binding by the ZAP-70 tSH2 domain may be an important rate-limiting step in regulating ZAP-70 activation [117, 184] .

Although partial phosphorylation of ITAMs allows ZAP-70 to localize on the membrane, it cannot initiate the T-cell signaling, indicating an added layer of proofreading preventing ZAP-70 activation. Mass spectrometry-based phosphoproteomics studies suggest that ZAP-70 does not activate or initiate T-cell signaling without binding to its ligand at TCR [173, 175, 185] . The C-terminal SH2 domain of ZAP-70 interacts with phosphatidylinositol 4,5-bisphosphate (PIP2) and PIP3 lipid in the membrane in a spatiotemporal manner priming the tSH2 domain to bind doubly phosphorylated ITAMs [186] . Subsequent phosphorylation of the tyrosine residues in interdomain B increases the retention time of ZAP-70 at the membrane [119] . The strength of TCR signaling is determined by the ZAP-70 dwell time. Following ZAP-70 recruitment to the TCR by Single-particle tracking, Lillemeier and colleagues showed that minutes (<10 min) after ITAM binding, during early T-cell activation, ZAP-70 is released from the TCR complex and translocated to the plasma membrane [118] . Mass spectroscopy analysis and immunoblot assay suggest that Y126 residue in tSH2 domain of ZAP-70 determines the half-life at the TCR. Autophosphorylation of Y126 decreases the affinity of the tSH2 domain for phosphorylated ITAM, thus releasing the ZAP-70 from the TCR complex [118, 187, 188] . The signaling is again initiated by recruiting new ZAP-70 molecules to the TCR complex following a 'catch-and-prey' model [118] . At the membrane, ZAP-70 phosphorylates the substrate peptide in the LAT with high specificity. The kinase domain of ZAP-70 carries a high net positive charge at the substrate binding site that allows specific binding of the negatively charged substrates like LAT and SLP-76 [78] . It has also been established that Lck-dependent ZAP-70 phosphorylation mediates the adaptor function of Lck, essential for bringing LAT to the TCR for activation [84, 173, 175, 189] . The net negative charge in the substrate-binding site of Lck prevents transactivation of LAT [78] .

The LAT is an essential scaffold that coordinates early TCR signaling to downstream cellular responses in a phosphorylation-dependent manner. At the plasma membrane LAT and its binding partners colocalize into micrometer or submicrometer clusters [190] . Elimination of these microclusters by deleting key components (for example, LAT or Grb2) impairs downstream signaling and transcriptional responses [191] .

Several phosphorylation sites on LAT are vital for kinetic proofreading TCR response to antigen binding ( Figure  2 ). Among them, relatively slower phosphorylation of Y132 in LAT creates a critical kinetic bottleneck in transducing signaling downstream [84] . ZAP-70 phosphorylates Y132, which serves as a docking site for a PLC-γ1. The slower phosphorylation of Y132 is due to residue G131 located at the −1 position from Y132. Glycine at this position reduces the net negative charge of the peptide, making it a poor substrate for ZAP-70. Replacing G131 with an acidic amino acid accelerates the phosphorylation rate of Y132 and increases the PLC-γ1 activation, causing TCR to activate even with weak agonists or self-peptides [78, 84] .

ZAP-70 also phosphorylates several distal tyrosine residues on LAT (Y171, Y191, and Y226) that facilitate the recruitment for the Grb2 family of proteins, Tec family tyrosine kinase interleukin 2 inducible T-cell kinase (Itk) and SLP-76 [192] [193] [194] . The adaptor protein SLP-76 mediates the TCR response to cell migration. At the LAT complex, the SLP-76 is phosphorylated by ZAP-70, resulting in phosphorylation of Vav-1, a critical step in regulating T-cell migration [195] .

Recruitment of Itk to the signalosome connects the TCR signaling to the Ca 2+ response. At the TCR complex, Lck activates Itk by phosphorylating Y511 residue in the activation loop leading to autophosphorylation of Y180 on the SH3 domain [196, 197] . Next, the activated Itk phosphorylates two tyrosine residues, 775 and 783, respectively, turning on the catalytic domain of PLC-γ1 [198, 199] . PLC-γ1 cleaves PIP2 into two secondary messengers, inositol 1,4,5-trisphosphate (IP3) and DAG (Figure 1 ). IP3 then interacts with its cognate IP3 receptors (IP3R) on the endoplasmic reticulum (ER), inducing Ca 2+ influx to the cytoplasm. Increased cytoplasmic Ca 2+ activates the calcineurin by removing the inhibitory interaction with the calmodulin (Figure 1 ). The free calcineurin is now available to dephosphorylate cytoplasmic localized nuclear factor of activated T cells (NFAT) (Figure 1 ) [121] . PLC-γ1 and LAT interaction shields the phosphotyrosine residues on LAT from dephosphorylation by CD45, providing enough time to propagate downstream signaling by activating Erk through multiple pathways [200, 201] . An alternate pathway mediated by a ternary complex among PLC-γ1, Pak1, and Bam32 also activates Erk, independently of LAT [202] . Erk plays a central role in connecting TCR response to the downstream gene expression (Figure 1) . Additionally, Erk also functions as a negative feedback regulator of TCR signaling. The Erk phosphorylates T155 residue on LAT, thereby preventing recruitment of PLC-γ1 [203] .

Immediately after the pMHC engagement, TCRs oligomerize into microcluster to which the TCR, ZAP-70, and LAT-associated signaling modules are recruited sequentially [204, 205] (Figures 1 and 2) . The multiple phosphorylation sites on the LAT enable cross-linking of LAT-associated signaling modules driving the microcluster formation [192, 206] . In a recent study, Yi and colleagues observed a kinetic lag (delayed recruitment) in ZAP-70 binding to TCR and subsequent LAT recruitment to the ZAP-70-bound TCR complex [181] . The observed delays in recruiting the downstream signaling module may be an essential component in regulating kinetic proofreading in T cells ( Figure  2 ). The elevated intracellular Ca 2+ flux negatively regulates the TCR signaling by increasing the kinetic lag of ZAP-70 and LAT recruitment to the TCR microcluster.

Immunometabolism has emerged as an integral regulator of immune cell responses. T lymphocytes acquire separate functional lineages on activation, and each functionally distinct states have specific metabolic requirements [207] . The naive T cells mostly remain in the quiescent stage. When activated, metabolic network is rewired to meet the demands of cytoskeletal rearrangement, clonal expansion, and epigenetic remodeling [208, 209] . The naive T cell depends on lipid and pyruvate oxidation for survival [209] and converts into aerobic glycolysis and glutamine oxidation upon activation to sustain proliferation and rapid cell growth (Figure 3 ) [207] . The interplay between immune signaling pathways and metabolic changes is bidirectional [210] . The TCR signaling regulates metabolism, and the metabolites directly influence signaling modules or epigenetic remodeling to alter different cellular processes (Figure 3 ) [211] . The involvement of bidirectional metabolic signaling in regulating T-cell quiescence and activation has been extensively reviewed [208] . In T cells, the metabolite utilization is mainly regulated through the costimulatory CD28 receptor via the PI3K-Akt-mTOR pathway (Figures 1 and 3 ) [212] [213] [214] . TCR signaling on pMHC binding and CD28 costimulatory pathways up-regulates the expression of glucose transporter, GLUT 1, crucial for glucose uptake [215] [216] [217] . Using a genome-wide CRISPR screening and protein-protein interaction network mapping, Long and colleagues 

The naive and activated T cells are labeled. The resting naive T cells metabolize glucose primarily via the high energy-yielding mitochondrial oxidative phosphorylation pathway. On activation, the glucose uptake is enhanced due to up-regulation of GLUT1 expression. The cells switch to aerobic glycolysis and lipid oxidation to produce biosynthetic precursors, this enhancing cell growth and proliferation. The TCR signaling modules cross-talk with the glucose metabolism are shown.

have identified key immune regulators that connect immune receptors to the nutrient-dependent downstream mammalian target of rapamycin (mTOR) signaling cascade [218] . However, the influence of early TCR signaling outputs on the metabolic network is not fully understood.

In a recent study, Jones and colleagues investigated the effect of TCR: antigen-binding affinity on the metabolic output in T cells [160, 219] . Studying peptide-human leukocyte antigen (pHLA) and TCR binding, they concluded that the most robust ligand interaction might result in the highest glycolic change and hexokinase expression. Downstream TCR signaling modules play a crucial role in cross-talk with the metabolic network. Erk, which is activated downstream of the TCR signaling, regulates glucose utilization by enhancing hexokinase gene expression [220, 221] . However, if hexokinase is a direct phosphorylation target of Erk is unknown. Alternatively, hexokinase II (HK-II) activation is also regulated by Akt [222, 223] . Dynamic localization of HK-II between the cytosol and mitochondria is important for maintaining cellular energy balance (i.e. catabolism vs anabolism). Phosphorylation of HK-II by Akt promotes localization of HK-II to the mitochondria leading to increase glycolytic flux and catabolism. Together, these observations suggest that both Erk and phosphatidylinositol 3-kinase (PI3K)-Akt pathways may synergistically regulate hexokinase-dependent glucose metabolism upon TCR activation (Figure 3 ). Calcium ion (Ca 2+ ) is another signaling modulator downstream of TCR that regulates the metabolic network of T cells. For example, a defect in the store-operated Ca 2+ entry (SOCE) pathway, which influences Ca 2+ flux in T cells, inhibits the phosphorylation of Akt and nutrient sensing through the mTOR pathway [224] .

Elevated potassium ion concentration in the tumor microenvironment is also linked to Ca 2+ homeostasis, which reprograms glycolysis and suppresses T-cell function. Increased potassium ion down-regulates Akt activation Impaired Lck inhibition Acute coronary syndrome [247] Missense mutation c.1022T>C New form of T-cell immunodeficiency [248] CD3ζ

Reduced expression Renal cell carcinoma [249] Reduced expression Colorectal carcinoma [250] Reduced expression Rheumatoid arthritis (RA) [251] Reduced or lack of expression Systemic lupus erythemetosus (SLE) [252] ZAP-70 Abnormal ZAP-70 expression in B cells Chronic lymphocytic leukemia (CLL) [237] Deficiency Severe combined immunodeficiency (SCID) [236] W163C mutation (mice) Rheumatoid arthritis in SKG mice [183] R192W, R360P mutation Undescribed human ZAP-70-associated autoimmune disease [253] P80Q/M572L CD8+ lymphopenia [254] L337R Secondary hemophagocytic syndrome [255] D521N Immune thrombocytopenic purpura [256] c.1623 + 5G > A Epstein-Barr virus (EBV) lymphoproliferative disease (LPD), Hemophagocytic lymphohistiocytosis (HLH) [257] LAT Up-regulation Sezary syndrome [258] Frameshift mutation (c.44 45insT;p.Leu16AlafsX28) T − B + NK + SCID [259] Y136F mice Lymphoproliferative syndrome [260] ITK Deficiency and R29H mutation EBV-associated lymphoproliferative disease [261] PLC-γ1 P L C γ1-deficient mice Peripheral T-cell lymphopenia [262] through serine-threonine phosphatase PP2A-dependent manner, affecting the nutrient-sensing mTOR pathway and down-regulating glucose uptake [225] . The reduction in nutrient uptake forces T cells to enter a functional caloric restriction state, thus driving mitochondrially dominant metabolism. Low nutrition leads to scarcity of cofactors like nucleocytosolic acetyl-coenzyme A limiting the acetylation of histone H3, required to promote effector functions. Depletion of methionine intermediates under starvation lowers the methylation of Histone H3 is linked to T-cell stemness [226] . Together, these observations indicate that extracellular and intracellular nutrient levels can significantly impact T-cell functioning. Since the TCR-induced immunological cues and metabolic cascades are intricately connected, reprogramming metabolic pathways is a promising tool for improving T cell-based immunotherapies [227] .

Tight regulation of signaling pathways is imperative for an accurate immune response at the right time. The adaptive immune system evolved from a lymphoid cell-based systems in jawless vertebrates to a robust BCR-TCR-MHC immune system in jawed vertebrates [25, 30, [228] [229] [230] . The humoral and cell-mediated parts of the adaptive immune system are governed by B and T cells, respectively [231, 232] . Both the cell types share the same lineage, and the same family of proteins mediate the receptor-dependent downstream signaling following a conceptually similar mechanism [231, 233] . For example, like T cells, the early receptor signaling in B cell is initiated by Src and Syk family of non-receptor tyrosine kinases [234] . B-cell receptor signaling begins with Syk kinase recruitment, corresponding to ZAP-70 activation in TCR signaling. Despite the high sequence conservation between Syk and ZAP-70, the functional significance of the subtle difference between the two proteins in determining the respective cellular response is not clearly understood [234] [235] [236] . Chronic lymphocytic leukemia (B-CLL) aberrantly expresses ZAP-70, remodels the Syk-mediated BCR downstream signaling. ZAP-70 diverts the B cells to undergo tonic PI3K signaling and ensures cell survival, promoting malignancy [237, 238] . Deregulation of crucial signaling modules in TCR signaling pathways ( Figure 1 ) often associated with human diseases related to cellular anergy, immunodeficiency or autoimmune diseases (summarized in Table 1 ). Over the years, immunotherapy and immunomodulators have evolved as a potent therapeutic strategy to treat autoimmune disorders and cancer [227] . The ability of T cells to identify tumor antigens and drive antitumor activities makes adoptive cellular transfer (ACT) therapy an essential clinical approach in multiple cancer treatments [239] . Promising clinical approaches of using immunotherapies like chimeric antigen receptor T cells (CAR T) therapy, TCR engineered T-cell therapy (TCR-T), and tumor-infiltrating lymphocytes (TILs) in mitigating multiple viral, autoimmune, and malignant diseases are being developed [240] [241] [242] [243] . Recent studies on SARS-CoV-2 patients revealed that elevated glucose levels and glycolysis facilitate increased viral replication and cause monocytes-driven cytokine storms, resulting in T-cell dysfunction [244, 245] . Together these observations underline the importance of investigating intricate networks and cross-talk between metabolic pathways and immune signaling to understand the regulation of the adaptive immune system.

The authors declare that there are no competing interests associated with the manuscript. 

K.G., S.R., S.S.G., A.C.C., and S.C. collected the material. K.G., S.R., S.S.G., A.C.C., S.C., and R.D. prepared the manuscript. R.D. edited the manuscript and supervised.

DAG, diacylglycerol; Erk, extracellular signal-regulated kinase; Grb2, growth factor receptor-bound protein 2; HK-II, hexokinase II; IP3, inositol 1,4,5-trisphosphate; ITAM, immunoreceptor tyrosine-based activation motif; Itk, interleukin 2 inducible T-cell kinase; LAT, linker for activation of T cells; Lck, lymphocyte-specific protein tyrosine kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC-γ1, phospholipase C-γ1; pMHC, peptide-major histocompatibility complex; SLP-76, SH2 domain containing leukocyte protein of 76 kDa; TCR, T-cell receptor; tSH2, two SH2 domains; UD, unique domain; ZAP-70, zeta chain-associated protein tyrosine kinase.

T-cell antigen receptor genes and T-cell recognition

Structure/function analysis of the invariant subunits of the T cell antigen receptor

Low affinity interaction of peptide-MHC complexes with T cell receptors

Deconstructing the peptide-MHC specificity of T cell recognition

The signaling symphony: T cell receptor tunes cytokine-mediated T cell differentiation

TCR signaling in T cell memory

TCR signaling: mechanisms of initiation and propagation

The T-cell antigen receptor. Structure and mechanism of activation

Acquisition of a functional T cell receptor during T lymphocyte development is enforced by HEB and E2A transcription factors

Human T cell development, localization, and function throughout life

Selecting and maintaining a diverse T-cell repertoire

The T-cell repertoire is heavily influenced by tolerance to polymorphic self-antigens

T cell receptor/MHC interactions in the thymus and the shaping of the T cell repertoire

Development and selection of T cells: facts and puzzles

Specificity of thymic selection and the role of self antigens

Positive selection of thymocytes

Positive and negative selection invoke distinct signaling pathways

Negative selection-clearing out the bad apples from the T-cell repertoire

The thymus and central tolerance

Quantitative impact of thymic clonal deletion on the T cell repertoire

Using thymus anatomy to dissect T cell repertoire selection

Chapter 22 -Infections, immunity, and autoimmunity

Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex

Evolution of innate and adaptive immune systems in jawless vertebrates

Origin and evolution of the adaptive immune system: genetic events and selective pressures

Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes

Transcriptome analysis of hagfish leukocytes: a framework for understanding the immune system of jawless fishes

Variable lymphocyte receptors in hagfish

Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase

The evolution of adaptive immune systems

Coreceptors and TCR signaling -the strong and the weak of it

Complex complexes: signaling at the TCR

A logical model provides insights into T cell receptor signaling

How TCRs bind MHCs, peptides, and coreceptorS

Roles of Lck, Syk and ZAP-70 tyrosine kinases in TCR-mediated phosphorylation of the adapter protein Shc

How does the kinase Lck phosphorylate the T cell receptor? Spatial organization as a regulatory mechanism

The role of adapter proteins in T cell activation

The clinical aspect of adaptor molecules in T cell signaling: lessons learnt from inborn errors of immunity

A stretch of negatively charged amino acids of linker for activation of T-cell adaptor has a dual role in T-cell antigen receptor intracellular signaling

Kinetic proofreading in T-cell receptor signal transduction

Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor

A cycle of Zap70 kinase activation and release from the TCR amplifies and disperses antigenic stimuli

Structural basis of assembly of the human T cell receptor-CD3 complex

Evidence for the T3-associated 90K heterodimer as the T-cell antigen receptor

Structural biology of the T-cell receptor: insights into receptor assembly, ligand recognition, and initiation of signaling

Insights into the initiation of TCR signaling

ZAP-70 in signaling, biology, and disease

Sequestration of CD4-associated Lck from the TCR complex may elicit T cell hyporesponsiveness in nonobese diabetic mice

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

The organizing principle in the formation of the T cell receptor-CD3 complex

Molecular mechanisms for the assembly of the T cell receptor-CD3 complex

Elementary steps in T cell receptor triggering

Non-catalytic tyrosine-phosphorylated receptors

TCR-pMHC kinetics under force in a cell-free system show no intrinsic catch bond, but a minimal encounter duration before binding

The discriminatory power of the T cell receptor

Intrinsic disorder in the T cell receptor creates cooperativity and controls ZAP70 binding

ZAP-70 association with T cell receptor zeta (TCRzeta): fluorescence imaging of dynamic changes upon cellular stimulation

Regulation of ZAP-70 intracellular localization: visualization with the green fluorescent protein

Fine-tuning T cell receptor signaling to control T cell development

How the T cell receptor sees antigen-a structural view

Regulation of TCR signalling by tyrosine phosphatases: from immune homeostasis to autoimmunity

Protein kinases and phosphatases in the control of cell fate

Signaling in lymphocyte activation

TCR activation kinetics and feedback regulation in primary human T cells

T-cell receptor binding affinities and kinetics: impact on T-cell activity and specificity

Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker

ZAP-70: an essential kinase in T-cell signaling

Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function

ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain

ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR zeta in murine thymocytes and lymph node T cells

Phosphatase CD45 both positively and negatively regulates T cell receptor phosphorylation in reconstituted membrane protein clusters

CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signaling

Changes in the role of the CD45 protein tyrosine phosphatase in regulating Lck tyrosine phosphorylation during thymic development

THEMIS-SHP1 recruitment by 4-1BB tunes LCK-mediated priming of chimeric antigen receptor-redirected T cells

Encoding optical control in LCK kinase to quantitatively investigate its activity in live cells

Constitutively active Lck kinase in T cells drives antigen receptor signal transduction

Light-based tuning of ligand half-life supports kinetic proofreading model of T cell signaling

An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor

Positive feedback between the T cell kinase Zap70 and its substrate LAT acts as a clustering-dependent signaling switch

T cell activation

Signaling pathways that regulate T cell development and differentiation

Distinct TCR signaling pathways drive proliferation and cytokine production in T cells

LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathways

Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination

Enhanced function of redirected human T cells expressing linker for activation of T cells that is resistant to ubiquitylation

Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells

The integrin LFA-1 signals through ZAP-70 to regulate expression of high-affinity LFA-1 on T lymphocytes

Chemokine-induced Zap70 kinase-mediated dissociation of the Vav1-talin complex activates alpha4beta1 integrin for T cell adhesion

Quantitation of antigen-presenting cell MHC class II/peptide complexes necessary for T-cell stimulation

MHC class II structure, occupancy and surface expression determined by post-endoplasmic reticulum antigen binding

Protocol for barcoding T cells combined with timed stimulations

Tonic signals: why do lymphocytes bother?

ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR ζ in murine thymocytes and lymph node T cells

Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease

The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function

Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling

T cell receptor structures: three for the price of one

Initiation of TCR phosphorylation and signal transduction

Positive and negative selection of T cells

A perspective on the role of computational models in immunology

Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells

ITAMs versus ITIMs: striking a balance during cell regulation

Serial triggering of many T-cell receptors by a few peptide-MHC complexes

The serial engagement model 17 years after: from TCR triggering to immunotherapy

T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex

The efficiency of antigen recognition by CD8 + CTL clones is determined by the frequency of serial TCR engagement

The balance between T cell receptor signaling and degradation at the center of the immunological synapse is determined by antigen quality

Serial triggering of T cell receptors results in incremental accumulation of signaling intermediates

Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex

Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation

Serial triggering model

T cell receptor mechanosensing forces out serial engagement

CD28 and CD3 have complementary roles in T-cell traction forces

Cytotoxic T cells use mechanical force to potentiate target cell killing

Cytoskeletal forces during signaling activation in Jurkat T-cells

Mechanosensing drives acuity of αβ T-cell recognition

Progressive enhancement of kinetic proofreading in T cell antigen discrimination from receptor activation to DAG generation

A cycle of Zap70 kinase activation and release from the TCR amplifies and disperses antigenic stimuli

T cell receptor dwell times control the kinase activity of Zap70

Kinetic discrimination in T-cell activation

Signal transduction by lymphocyte antigen receptors

The role of tyrosine kinases and phosphotyrosine-containing recognition motifs in regulation of the T cell-antigen receptor-mediated signal transduction pathway

Regulation of pp56lck during T-cell activation: functional implications for the src-like protein tyrosine kinases

The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex

Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck

Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation

Structure determination of human Lck unique and SH3 domains by nuclear magnetic resonance spectroscopy

Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors

Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck

Structure of the regulatory domains of the Src-family tyrosine kinase Lck

A phosphosite within the SH2 domain of Lck regulates its activation by CD45

Regulation of src family tyrosine kinases in lymphocytes

Negative regulation of T-cell receptor signalling by tyrosine protein kinase p50csk

Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor

Serine 6 of Lck tyrosine kinase: a critical site for Lck myristoylation, membrane localization, and function in T lymphocytes

Fatty acyl chain-dependent but charge-independent association of the SH4 domain of Lck with lipid membranes

The role of membrane rafts in Lck transport, regulation and signalling in T-cells

Lck activation: puzzling the pieces together

De novo phosphorylation and conformational opening of the tyrosine kinase Lck act in concert to initiate T cell receptor signaling

The pool of preactivated Lck in the initiation of T-cell signaling: a critical re-evaluation of the Lck standby model

Beyond TCR signaling: emerging functions of Lck in cancer and immunotherapy

Distinct mechanisms regulate Lck spatial organization in activated T cells

Tyrosine 192 within the SH2 domain of the Src-protein tyrosine kinase p56(Lck) regulates T-cell activation independently of Lck/CD45 interactions

Recent insights of T cell receptor-mediated signaling pathways for T cell activation and development

Phosphorylation of Ser-42 and Ser-59 in the N-terminal region of the tyrosine kinase p56lck

Recruitment of calcineurin to the TCR positively regulates T cell activation

TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways

A THEMIS:SHP1 complex promotes T-cell survival

Stimulatory effects of the protein tyrosine phosphatase inhibitor, pervanadate, on T-cell activation events

The p56lck SH2 domain mediates recruitment of CD8/p56lck to the activated T cell receptor/CD3/zeta complex

The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck

Zinc is essential for binding of p56(lck) to CD4 and CD8alpha

The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes

A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8

The kinetic-segregation model: TCR triggering and beyond

Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation

CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development

Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases

Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance

Ionic CD3-Lck interaction regulates the initiation of T-cell receptor signaling

Proofreading through spatial gradients

Insights into the initiation of TCR signaling

Allosteric activation of T cell antigen receptor signaling by quaternary structure relaxation

Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling

Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif

Structural basis for the inhibition of tyrosine kinase activity of ZAP-70

The zeta chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein

The Syk/ZAP-70 protein tyrosine kinase connection to antigen receptor signalling processes

Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor

The structural basis for activation and inhibition of ZAP-70 kinase domain

Analysis of the interaction of ZAP-70 and syk protein-tyrosine kinases with the T-cell antigen receptor by plasmon resonance

Interdomain B in ZAP-70 regulates but is not required for ZAP-70 signaling function in lymphocytes

Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker

Crystal structure and NMR studies of the apo SH2 domains of ZAP-70: two bikes rather than a tandem

Intramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases

Phosphorylation of Tyr319 in ZAP-70 is required for T-cell antigen receptor-dependent phospholipase C-gamma1 and Ras activation

The structure, regulation, and function of ZAP-70

Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck

An allosteric hot spot in the tandem-SH2 domain of ZAP-70 regulates T-cell signaling

A micropatterning platform for quantifying interaction kinetics between the T cell receptor and an intracellular binding protein

TCR microclusters form spatially segregated domains and sequentially assemble in calcium-dependent kinetic steps

Molecular mechanism of selective recruitment of Syk kinases by the membrane antigen-receptor complex

Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice

An evolutionary divergent thermodynamic brake in ZAP-70 fine-tunes the kinetic proofreading in T cell. bioRxiv 1-31

The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway

SH2 domains serve as lipid-binding modules for pTyr-signaling proteins

Fine-tuning of proximal TCR signaling by ZAP-70 tyrosine residues in Jurkat cells

TCR signaling: mechanisms of initiation and propagation

Mechanisms determining a differential threshold for sensing Src family kinase activity by B and T cell antigen receptors

Cutting edge: cell surface linker for activation of T cells is recruited to microclusters and is active in signaling

Essential role of LAT in T cell development

Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1

Grap negatively regulates T-cell receptor-elicited lymphocyte proliferation and interleukin-2 induction

Minimal requirement of tyrosine residues of linker for activation of T cells in TCR signaling and thymocyte development

Regulation of Vav-SLP-76 binding by ZAP-70 and its relevance to TCR zeta/CD3 induction of interleukin-2

Itk phosphorylation sites are required for functional activity in primary T cells*

Positive regulation of Itk PH domain function by soluble IP4

A new tyrosine phosphorylation site in PLCγ1: the role of tyrosine 775 in immune receptor signaling

SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK

PLCγ1 promotes phase separation of T cell signaling components

Compartmentalized Ras/MAPK signaling

LAT-independent Erk activation via Bam32-PLC-gamma1-Pak1 complexes: GTPase-independent Pak1 activation

Negative feedback loop in T-cell activation through MAPK-catalyzed threonine phosphorylation of LAT

T cell receptor ligation induces the formation of dynamically regulated signaling assemblies

Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling

Multipoint binding of the SLP-76 SH2 domain to ADAP is critical for oligomerization of SLP-76 signaling complexes in stimulated T cells

Metabolic regulation of T lymphocytes

Metabolic coordination of T cell quiescence and activation

Metabolic signaling in T cells

Metabolic dysregulations and epigenetics: a bidirectional interplay that drives tumor progression

The bidirectional relationship between metabolism and immune responses

Glucose metabolism regulates T cell activation, differentiation, and functions

The CD28 signaling pathway regulates glucose metabolism

Unraveling the complex interplay between T cell metabolism and function

Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking

Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways

The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function

CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity

Metabolic adaptation of human CD4+ and CD8+ T-cells to T-cell receptor-mediated stimulation

Induction of glucose metabolism in stimulated T lymphocytes is regulated by mitogen-activated protein kinase signaling

Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation

Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II

Subcellular localization of hexokinases I and II directs the metabolic fate of glucose

Store-operated Ca2+ entry controls clonal expansion of T cells through metabolic reprogramming

Ionic immune suppression within the tumour microenvironment limits T cell effector function

T cell stemness and dysfunction in tumors are triggered by a common mechanism

Fundamentals of T cell metabolism and strategies to enhance cancer immunotherapy

Big Bang' emergence of the combinatorial immune system

Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey

Evolution of alternative adaptive immune systems in vertebrates

T and B lymphocytes and immune responses

B lymphocytes: how they develop and function

Composition and function of T-cell receptor and B-cell receptor complexes on precursor lymphocytes

The SYK tyrosine kinase: a crucial player in diverse biological functions

Differences in the dynamics of the tandem-SH2 modules of the Syk and ZAP-70 tyrosine kinases

ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency

Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia

Cooperation between SYK and ZAP70 kinases as a driver of oncogenic BCR-signaling in B-cell malignancies

Adoptive cell transfer: a clinical path to effective cancer immunotherapy

CAR T-cell therapy: a new era in cancer immunotherapy

Engineered T cell therapy for cancer in the clinic

The biologic importance of tumor-infiltrating lymphocytes

Evolution of CD8+ T cell receptor (TCR) engineered therapies for the treatment of cancer

Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis

The cytokine profiles and immune response are increased in COVID-19 patients with type 2 diabetes mellitus

Mislocalization of Lck impairs thymocyte differentiation and can promote development of thymomas

Insufficient deactivation of the protein tyrosine kinase lck amplifies T-cell responsiveness in acute coronary syndrome

Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency

Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma

Decreased expression of the signal-transducing zeta chains in tumor-infiltrating T-cells and NK cells of patients with colorectal carcinoma

Evidence for the role of an altered redox state in hyporesponsiveness of synovial T cells in rheumatoid arthritis

Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain

A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70

Temperature-sensitive ZAP70 mutants degrading through a proteasome-independent pathway. Restoration of a kinase domain mutant by Cdc37

Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency

Novel mutation of ZAP-70-related combined immunodeficiency: First Case from the National Iranian Registry and Review of the Literature

Novel ZAP-70-related immunodeficiency presenting with Epstein-Barr virus lymphoproliferative disorder and hemophagocytic lymphohistiocytosis

Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes

Mutations in linker for activation of T cells (LAT) lead to a novel form of severe combined immunodeficiency

A LAT mutation that inhibits T cell development yet induces lymphoproliferation

Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases

Phospholipase C{gamma}1 is essential for T cell development, activation, and tolerance