8jbv
Extracellular domain of gamma delta TCR
Structural highlights
FunctionTRDV1_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).[1] [2] [3] [4] [5] TRDC_HUMAN Constant region 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).[6] [7] [8] [9] [10] Publication Abstract from PubMedGamma delta (gammadelta) T cells, a unique T cell subgroup, are crucial in various immune responses and immunopathology(1-3). The gammadelta T cell receptor (TCR), generated by gammadelta T cells, recognizes a diverse range of antigens independently of the major histocompatibility complex(2). The gammadelta TCR associates with CD3 subunits, initiating T cell activation and holding great potential in immunotherapy(4). Here, we report the structures of two prototypical human Vgamma9Vdelta2 and Vgamma5Vdelta1 TCR-CD3 complexes(5,6), unveiling two distinct assembly mechanisms that depend on Vgamma usage. The Vgamma9Vdelta2 TCR-CD3 complex is monomeric, with considerable conformational flexibility in the TCRgamma/TCRdelta extracellular domain (ECD) and connecting peptides (CPs). The length of CPs regulates the ligand association and T cell activation. Additionally, a cholesterol-like molecule wedges into the transmembrane region, exerting an inhibitory role in TCR signaling. The Vgamma5Vdelta1 TCR-CD3 complex displays a dimeric architecture, where two protomers nestle back-to-back via their Vgamma5 domains of TCR ECDs. Our biochemical and biophysical assays further corroborate the dimeric structure. Importantly, the dimeric form of the Vgamma5Vdelta1 TCR is essential for T cell activation. These findings reveal organizing principles of the gammadelta TCR-CD3 complex, providing insights into the gammadelta TCR unique properties and facilitating immunotherapeutic interventions. Structures of human gammadelta T cell receptor-CD3 complex.,Xin W, Huang B, Chi X, Liu Y, Xu M, Zhang Y, Li X, Su Q, Zhou Q Nature. 2024 Apr 24. doi: 10.1038/s41586-024-07439-4. PMID:38657677[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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