8yc0
T cell receptor V delta2 V gamma9 in GDNT cell receptor V delta2 V gamma9 in GDN
Structural highlights
DiseaseCD3D_HUMAN Defects in CD3D are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive (T(-)B(+)NK(+) SCID) [MIM:608971. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.[1] FunctionCD3D_HUMAN The CD3 complex mediates signal transduction. 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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