TCR signaling pathway

The T-cell antigen receptor (TCR) complex is composed of a ligand-binding subunit, the α and β chains, and a signaling subunit, namely the CD3ε, γ and δ chains and the TCRζ chain. This complex participates in T-cell activation upon the presentation of the antigen peptide (derived from the foreign antigen) bound to the MHC (Class I and Class II) residing on antigen-presenting cells (APCs), including dendritic cells, macrophages and B cells. Co-stimulatory receptors, such as CD2, CD28, CD4, CD8, and integrin molecules, contribute to signal transduction by modulating the response threshold. All the above components along with accessory proteins essential for MHC are a part of the immunological synapse that initiates T-cell activation. Protein tyrosine phosphorylation mediated by the Src family kinases Lck and Fyn, in turn regulated by CD45, is the initial event in TCR signaling. Lck is activated by the interaction of MHC and CD4 or CD8. It then induces the phosphorylation and activation of TCR-CD3 complex and eventually mediates Fyn activation. The activated Src kinases phosphorylate ITAMs (Immune receptor tyrosine-based activation motifs) present on CD3γ, δ, ε and ζ chain. The 70-kd ζ chain–associated protein kinase (ZAP70) is then recruited to the ITAMs followed by its phosphorylation and subsequent activation which results in further amplification of the response. These activated PTKs induce tyrosine phosphorylation of several polypeptides, including the transmembrane adaptor LAT (Linker Activator for T-Cells). Protein tyrosine phosphorylation subsequently leads to the activation of multiple pathways, including ERK (Extracellular Signal Regulated Kinase), JNK (c-Jun N-terminal Kinase), NF-κB (Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) and NFAT(Nuclear Factor of Activated T-Cells) pathways, which ultimately induce effector functions. CD28 ligation by B7-1 or B7-2 helps in bringing the T-Cell and Antigen Presenting Cell membranes into close proximity. This event also provides a co-stimulatory signal leading to the production of IL-2 and T- cell activation. Besides CD28, many other transmembrane receptors also modulate specific elements of TCR signaling. CD28 and CD45 activate Lck which in turn induces the phosphorylation and activation of the TCR-CD3 complex and consequently, the tyrosine kinases Fyn and ZAP70. CD45 plays a role in antagonizing the effect of inhibitory proteins on T-cell activation. ZAP70 induces activation of LAT (Linker for Activation of T-Cells), an integral membrane adaptor protein which further binds to GADS (Growth Factor Receptor-Bound Protein-2-Related Adaptor Protein-2), SLP76 (SH2 Domain-Containing Leukocyte Protein-76), and ITK (IL-2 inducible T-cell kinase). This complex facilitates the activation of PLCG1 (Phospholipase-C-Gamma1) that is responsible for the production of the second messengers DAG (Diacylglycerol) and IP3 (Inositol Triphosphate). DAG activates proteins including PKCθ (Protein Kinase-C-Theta) and Ras, whereas IP3 leads to Ca2+ release from ER and also facilitates influx of extracellular calcium. Increased intracellular Ca2+ activates the phosphatase Calcineurin that dephosphorylates NFAT which then enters the nucleus and promotes transcription. Activated LAT also binds multiple adaptor proteins including GRB2, GRAP (GRB2- Related Adaptor Protein) and GADS to facilitate activation of serine/threonine kinases such as Raf1, MEK (MAPK/ERK Kinase) and dual-specificity kinases ERK1/2 that are involved in activation of MAPKs (Mitogen activated protein kinases) resulting in the induction of transcription factor Elk1. ZAP70 also activates IKKs via the CARD11 (Caspase recruitment domain family, member 11) -BCL10 (B-Cell CLL/lymphoma-10)-MALT1 (Mucosa Associated Lymphoid Tissue Lymphoma Translocation Gene-1) complex and MAP3K (activated by PKCθ) which in turn relieve NF-κB of IκB (NF-kappa-B inhibitor beta) and allow its nuclear translocation and transcriptional activation. ZAP70 also activates p38 via Vav, Rac and MKK3/6 (Mitogen-Activated Protein Kinase Kinase-3 / Mitogen-Activated Protein Kinase Kinase-6). p38 then activates the transcription factor ATF2 (Activating Transcription Factor-2). Activated Rac also activates JNK via MEKK1 and MKK4/7 (MKK4 (Mitogen-Activated Protein Kinase Kinase-4/ Mitogen-Activated Protein Kinase Kinase-7) which eventually leads to activation of c-Jun mediated transcription. SIT (SHP2-Interacting Transmembrane Adaptor Protein) and CTLA4 (Cytotoxic T-Lymphocyte Antigen-4) are transmembrane adaptor proteins that interact with the SHP2 (SH2-containing Protein tyrosine Phosphatase-2) and negatively regulate T-cell activation by inhibiting the phosphorylation of Fyn and CD28 respectively. CTLA4 has a greater affinity for its B7-1/B7-2ligands in comparison toCD28 and thus competes for them. During T-cell activation CTLA4 is endocytosed to quicken the response. ZAP70 facilitates translocation of CTLA4 to the membrane when the response needs to be controlled. PAG (Phosphoprotein Associated with Glycosphingolipid Microdomains), a transmembrane adaptor molecule is associated with CSK (c-Src Tyrosine Kinase), an inhibitor of Src-related protein tyrosine kinases. Overexpression of PAG inhibits TCR-mediated responses. Dual specificity phosphatase 3 (DUSP3) or VHR is also induced by ZAP70 which consequently down regulates ERK activation and thus controls T-cell response. Please access this pathway at [http://www.netpath.org/netslim/tcr_pathway.html NetSlim] database.

T细胞抗原受体（TCR）复合体由配体结合亚基，即α和β链，以及信号传导亚基，包括CD3ε、γ、δ链和TCRζ链组成。该复合体在抗原呈递细胞（APC），如树突状细胞、巨噬细胞和B细胞上，MHC（I类和II类）所驻留的抗原肽（源自外源性抗原）结合后，参与T细胞活化。共刺激受体，如CD2、CD28、CD4、CD8和整合素分子，通过调节反应阈值，参与信号传导。所有上述成分以及对于MHC不可或缺的辅助蛋白，共同构成了启动T细胞活化的免疫突触。Src家族激酶Lck和Fyn介导的蛋白质酪氨酸磷酸化，进而受到CD45的调控，是TCR信号传导的初始事件。Lck通过MHC与CD4或CD8的相互作用而被激活，随后诱导TCR-CD3复合体的磷酸化和激活，并最终介导Fyn的激活。激活的Src激酶在CD3γ、δ、ε和ζ链上磷酸化ITAMs（免疫受体酪氨酸基激活基序）。随后，70-kd的ζ链相关蛋白激酶（ZAP70）被招募至ITAMs，并随后发生磷酸化和激活，这导致响应的进一步放大。这些激活的PTKs诱导多种多肽的酪氨酸磷酸化，包括跨膜适配器LAT（T细胞连接激活因子）。蛋白质酪氨酸磷酸化随后导致包括ERK（细胞外信号调节激酶）、JNK（c-Jun N-端激酶）、NF-κB（κ轻链基因增强子B细胞核因子1）和NFAT（激活的T细胞核因子）在内的多条途径的激活，这些途径最终诱导效应功能。CD28通过B7-1或B7-2的连接，有助于将T细胞和抗原呈递细胞膜拉近。这一事件还提供了一个共刺激信号，导致IL-2的产生和T细胞的活化。除了CD28之外，许多其他跨膜受体也调节TCR信号传导的特定元素。CD28和CD45激活Lck，进而诱导TCR-CD3复合体的磷酸化和激活，以及酪氨酸激酶Fyn和ZAP70的激活。CD45在拮抗抑制蛋白对T细胞活化的影响方面发挥作用。ZAP70诱导LAT（T细胞激活连接因子）的激活，LAT是一种整合膜适配蛋白，它进一步与GADS（生长因子受体结合蛋白-2相关适配蛋白-2）、SLP76（含SH2结构域的白细胞蛋白-76）和ITK（IL-2诱导T细胞激酶）结合。此复合体促进PLCG1（磷脂酰肌醇-γ激酶-C1）的激活，PLCG1负责产生第二信使DAG（二酰甘油）和IP3（肌醇三磷酸）。DAG激活包括PKCθ（蛋白激酶-C-θ）和Ras在内的蛋白质，而IP3导致ER中的Ca2+释放，并促进细胞外钙的流入。细胞内Ca2+的增加激活了磷酸酶Calcineurin，Calcineurin去磷酸化NFAT，随后NFAT进入细胞核并促进转录。激活的LAT还与包括GRB2、GRAP（GRB2相关适配蛋白）和GADS在内的多种适配蛋白结合，以促进丝氨酸/苏氨酸激酶，如Raf1、MEK（MAPK/ERK激酶）和双特异性激酶ERK1/2的激活，这些激酶参与MAPKs（丝裂原活化蛋白激酶）的激活，从而诱导转录因子Elk1的激活。ZAP70还通过CARD11（Caspase募集域家族成员11）-BCL10（B细胞CLL/淋巴瘤-10）-MALT1（黏膜相关淋巴组织淋巴瘤易位基因-1）复合体和MAP3K（由PKCθ激活）激活IKKs，这些复合体和激酶随后解除NF-κB的IκB（NF-kappa-B抑制蛋白β）的抑制，允许其核转位和转录激活。ZAP70还通过Vav、Rac和MKK3/6（丝裂原活化蛋白激酶激酶-3/丝裂原活化蛋白激酶激酶-6）激活p38，然后p38激活转录因子ATF2（激活转录因子-2）。激活的Rac还通过MEKK1和MKK4/7（MKK4（丝裂原活化蛋白激酶激酶-4/丝裂原活化蛋白激酶激酶-7））激活JNK，最终导致c-Jun介导的转录激活。SIT（SHP2-相互作用跨膜适配蛋白）和CTLA4（细胞毒性T淋巴细胞抗原-4）是跨膜适配蛋白，它们与SHP2（含SH2结构域的蛋白质酪氨酸磷酸酶-2）相互作用，并通过抑制Fyn和CD28的磷酸化来负向调节T细胞活化。与CD28相比，CTLA4对其B7-1/B7-2配体的亲和力更高，因此与之竞争。在T细胞活化过程中，CTLA4被内吞以加快响应。当需要控制响应时，ZAP70促进CTLA4向膜转位。PAG（与糖鞘脂微域相关的磷酸蛋白）是一种跨膜适配分子，与CSK（c-Src酪氨酸激酶）相关联，CSK是Src相关蛋白酪氨酸激酶的抑制剂。PAG的过表达抑制TCR介导的响应。双特异性磷酸酶3（DUSP3）或VHR也被ZAP70诱导，从而下调ERK的激活，从而控制T细胞反应。请访问[http://www.netpath.org/netslim/tcr_pathway.html NetSlim]数据库获取此途径。