7ryn
CD1a-sulfatide-gdTCR complex
Structural highlights
DiseaseTRAC_HUMAN TCR-alpha-beta-positive T-cell deficiency. The disease is caused by variants affecting the gene represented in this entry. FunctionTRAC_HUMAN Constant region of T cell receptor (TR) alpha chain (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).[1] [2] [3] [4] TRDV1_HUMAN V region of the variable domain of T cell receptor (TR) delta chain that participates in the antigen recognition (PubMed:24600447). Gamma-delta TRs recognize a variety of self and foreign non-peptide antigens frequently expressed at the epithelial boundaries between the host and external environment, including endogenous lipids presented by MH-like protein CD1D and phosphoantigens presented by butyrophilin-like molecule BTN3A1. Upon antigen recognition induces rapid, innate-like immune responses involved in pathogen clearance and tissue repair (PubMed:23348415, PubMed:28920588). Binding of gamma-delta TR complex to antigen triggers phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3 chains by the LCK and FYN kinases, allowing the recruitment, phosphorylation, and activation of ZAP70 that facilitates phosphorylation of the scaffolding proteins LCP2 and LAT. This lead to the formation of a supramolecular signalosome that recruits the phospholipase PLCG1, resulting in calcium mobilization and ERK activation, ultimately leading to T cell expansion and differentiation into effector cells (PubMed:25674089). Gamma-delta TRs are produced through somatic rearrangement of a limited repertoire of variable (V), diversity (D), and joining (J) genes. The potential diversity of gamma-delta TRs is conferred by the unique ability to rearrange (D) genes in tandem and to utilize all three reading frames. The combinatorial diversity is considerably increased by the sequence exonuclease trimming and random nucleotide (N) region additions which occur during the V-(D)-J rearrangements (PubMed:24387714).[5] [6] [7] [8] [9] Publication Abstract from PubMedCD1a is a monomorphic antigen-presenting molecule on dendritic cells that presents lipids to alphabeta T cells. Whether CD1a represents a ligand for other immune receptors remains unknown. Here we use CD1a tetramers to show that CD1a is a ligand for Vdelta1(+) gammadelta T cells. Functional studies suggest that two gammadelta T cell receptors (TCRs) bound CD1a in a lipid-independent manner. The crystal structures of three Vgamma4Vdelta1 TCR-CD1a-lipid complexes reveal that the gammadelta TCR binds at the extreme far side and parallel to the long axis of the beta-sheet floor of CD1a's antigen-binding cleft. Here, the gammadelta TCR co-recognises the CD1a heavy chain and beta2 microglobulin in a manner that is distinct from all other previously observed gammadelta TCR docking modalities. The 'sideways' and lipid antigen independent mode of autoreactive CD1a recognition induces TCR clustering on the cell surface and proximal T cell signalling as measured by CD3zeta phosphorylation. In contrast with the 'end to end' binding of alphabeta TCRs that typically contact carried antigens, autoreactive gammadelta TCRs support geometrically diverse approaches to CD1a, as well as antigen independent recognition. Atypical sideways recognition of CD1a by autoreactive gammadelta T cell receptors.,Wegrecki M, Ocampo TA, Gunasinghe SD, von Borstel A, Tin SY, Reijneveld JF, Cao TP, Gully BS, Le Nours J, Moody DB, Van Rhijn I, Rossjohn J Nat Commun. 2022 Jul 5;13(1):3872. doi: 10.1038/s41467-022-31443-9. PMID:35790773[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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