A TCR β-Chain Motif Biases toward Recognition of Human CD1 Proteins

Abstract

High-throughput TCR sequencing allows interrogation of the human TCR repertoire, potentially connecting TCR sequences to antigenic targets. Unlike the highly polymorphic MHC proteins, monomorphic Ag-presenting molecules such as MR1, CD1d, and CD1b present Ags to T cells with species-wide TCR motifs. CD1b tetramer studies and a survey of the 27 published CD1b-restricted TCRs demonstrated a TCR motif in humans defined by the TCR b-chain variable gene 4-1 (TRBV4-1) region. Unexpectedly, TRBV4-1 was involved in recognition of CD1b regardless of the chemical class of the carried lipid. Crystal structures of two CD1b-specific TRBV4-1 + TCRs show that germline-encoded residues in CDR1 and CDR3 regions of TRBV4-1-encoded sequences interact with each other and consolidate the surface of the TCR. Mutational studies identified a key positively charged residue in TRBV4-1 and a key negatively charged residue in CD1b that is shared with CD1c, which is also recognized by TRBV4-1 TCRs. These data show that one TCR V region can mediate a mechanism of recognition of two related monomorphic Ag-presenting molecules that does not rely on a defined lipid Ag.

CD36 family members are TCR-independent ligands for CD1 antigen-presenting molecules

“…4G ). We also noted an enrichment of TRAV17 (5/26) in the TCR-α chain, a variable gene known to be enriched in a population of CD1b-restricted T cells 50, 51 , as well as TRAV38-1 (4/26).…”

SLAMF7 and IL-6R define distinct cytotoxic versus helper memory CD8+ T cells

“…However, we observed an enrichment of Vβ13 (TRBV6) and Vβ2 (TRBV20) families among Tc17 + 1 cells, of which up to 10% could be characterized as MAIT cells based on their co-expression of Vα7.2 and CD161 (Supplementary Fig. 6) 23,24 . A strong overlap of TCRβ-CDR3 clonotypes was demonstrated for the two cytotoxic Tc1 and Tc17 + 1 cell subsets and the three helper Tc2, Tc17, and Tc22 cell subsets covering 50% of total reads ( Fig.…”

Novel Molecular Insights into Human Lipid-Mediated T Cell Immunity

“…While significant headway has been made into understanding CD1b-restricted TCR recognition, presently much remains unknown. For instance, the mechanisms of TRBV4-1 TCR recognition, which include LDN5-like TCRs, are unknown, despite accounting for approximately 40% of known CD1b restricted TCRs, and exhibiting reactivity towards both bacterial- and self- lipid antigens [ 55 ]. Preliminary alanine-scanning mutagenesis and structural studies of TRBV4-1 TCRs reveal key amino acid residues in the CDR1β (His29β and Arg30β) and CDR2β (Tyr58β) regions that may directly contact CD1b or influence the positioning of the CDR3β region for antigen recognition [ 55 ].…”

“…For instance, the mechanisms of TRBV4-1 TCR recognition, which include LDN5-like TCRs, are unknown, despite accounting for approximately 40% of known CD1b restricted TCRs, and exhibiting reactivity towards both bacterial- and self- lipid antigens [ 55 ]. Preliminary alanine-scanning mutagenesis and structural studies of TRBV4-1 TCRs reveal key amino acid residues in the CDR1β (His29β and Arg30β) and CDR2β (Tyr58β) regions that may directly contact CD1b or influence the positioning of the CDR3β region for antigen recognition [ 55 ]. Furthermore, three CD1b-restricted γδTCRs encoding Vδ1 gene usage were identified, each exhibiting one of two distinct modes of recognition towards bacterial glycolipid BBGL2 lipid from Borrelia burgdorferi and a range of self-lipids, via ligand dependent or independent mechanisms [ 56 ].…”

“…In contrast, CD1c-autoreactive T cells have demonstrated a conserved TRBV4-1 gene usage, with a subset of CD4 + /TRBV4 + T cells characterized by CD154 upregulation and cytokine production [ 60 ]. Here, mutational mapping of the TRBV4-1 sequence revealed that Arg30β and Tyr51β play a crucial role for CD1c recognition, which shares some similarities to CD1b recognition by CD1b-restricted TCRs [ 55 ]. Furthermore, tetramers of CD1c-C32 PM are able to detect a subset of Vδ1 + γδ T cells from healthy PBMCs that demonstrate T cell activation.…”