Conserved T cell receptor usage underpins recognition of CD1c presenting a mycobacterial lipid

The mechanism by which T cell receptors (TCR) recognise mycobacterial lipids presented by CD1 family members not well understood. We used CD1c tetramers loaded with the mycobacterial phosphomycoketide (PM) or mannosyl-PM (MPM) to isolate T cells ex vivo in healthy blood donors and in individuals from a tuberculosis (TB)-endemic region of South Africa, with higher frequencies observed in individuals from the TB-endemic region. High throughput analysis of >200 paired CD1c-mycoketide tetramer+ {beta}TCRs identified a conserved TCR motif, encoded by TRBV4-1 or TRBV7-9 variable region genes in greater than half of TCRs sequenced. A cryo-EM structure of a TRBV7-9+ TCR in complex with CD1c-PM demonstrated that the TCR bound to the F side of CD1c, directly contacting the phospholipid antigen and F-portal residues. Analysis of multiple T cell clones interacting with CD1c mutants suggested that this TCR docking mode is representative of the larger TRBV7-9+ T cell population. Collectively, this study provides insight into mycobacterial lipid-antigen recognition by CD1c-restricted T cells. SummaryCao and Soliman et al study CD1c-restricted human T cells that recognize mycobacterial phosphomycoketide lipids, where they are shown to be more frequent in blood a TB-endemic region. The authors describe a strong TCR-{beta} repertoire bias and use cryoEM to provide a high-resolution structure of an archetypal TCR engaging CD1c in complex with a mycobacterial lipid.