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

Abstract

T cell activation requires extracellular stimulatory signals that are mainly mediated by T cell receptor (TCR) complexes. The TCR recognizes antigens on major histocompatibility complex molecules with the cooperation of CD4 or CD8 coreceptors. After recognition, TCR-induced signaling cascades that propagate signals via various molecules and second messengers are induced. Consequently, many features of T cell-mediated immune responses are determined by these intracellular signaling cascades. Furthermore, differences in the magnitude of TCR signaling direct T cells toward distinct effector linages. Therefore, stringent regulation of T cell activation is crucial for T cell homeostasis and proper immune responses. Dysregulation of TCR signaling can result in anergy or autoimmunity. In this review, we summarize current knowledge on the pathways that govern how the TCR complex transmits signals into cells and the roles of effector molecules that are involved in these pathways.

Fig. 1. Overview of T cell receptor signaling cascades.

ADAP adhesion and degranulation-promoting adapter protein, BCL B cell lymphoma, Cbl casitas B-lineage lymphoma, CaM calmodulin, CaMKIV calcium/calmodulin-dependent protein kinase type IV, CARMA1 caspase recruitment domain-containing membrane-associated guanylate kinase protein 1, Cdc42 cell division control protein 42, CRAC calcium release-activated calcium, CRBN cereblon, CREB cAMP response element-binding protein, CTLA-4 cytotoxic T lymphocyte-associated protein-4, DAG diacylglycerol, DEPTOR DEP domain-containing mTOR-interacting protein, Dlgh1 discs large homolog 1, ERK extracellular signal-related kinase, F-actin filamentous actin, GADD45α growth arrest and DNA damage inducible alpha, GβL G protein beta subunit-like, GRB2 growth factor receptor-bound protein 2, HPK1 hematopoietic progenitor kinase 1, IKK IκB kinase, IP₃ inositol triphosphate, IP₃R IP₃ receptor, JNK c-Jun N-terminal kinase, LAT linker for activation of T cells, Lck lymphocyte-specific protein tyrosine kinase, LFA-1 lymphocyte function-associated antigen-1, MALT1 mucosa-associated lymphoid tissue lymphoma translocation protein 1, MAPK mitogen-activated protein kinase, MEK MAPK/ERK kinase, MEKK MAP kinase kinase kinase, MKK MAP kinase kinase, mTOR mammalian target of rapamycin, NCK noncatalytic region of tyrosine kinase adaptor protein 1, NF-κB nuclear factor-κB, NFAT nuclear factor of activated T cells, PDK1 phosphoinositide-dependent kinase 1, PI3K phosphoinositide 3-kinase, PIP₂ phosphatidylinositol 4,5-bisphosphate, PKCθ protein kinase C theta, PLCγ1 phospholipase C gamma 1, Raptor regulatory-associated protein of mTOR, RasGRP Ras guanyl-releasing protein 1, SLP76 Src homology 2 domain containing leukocyte protein 76, SOS son of sevenless, TCR T cell receptor, WASP Wiskott–Aldrich syndrome protein, ZAP-70 zeta chain of TCR-associated protein 70, ZIP Zrt- and Irt-like protein.

Fig. 2. Transcriptional controls of T cell development.

CLP common lymphoid progenitor, DN double negative, DP double positive.