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bioRxiv · 10.64898/2026.06.17.733038

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

Cao, T.-P.·Soliman, C.·Redmond, S. J.·Tappen, T.·Kollmorgen, J.·Geng, Q.·Moody, D. B.·Scriba, T. J.·Uldrich, A. P.·Minnaard, A. J.·Seshadri, C.·Venugopal, H.·Shahine, A.·Rossjohn, J.·Godfrey, D. I.·Gherardin, N. A.
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Abstract

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.

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Cao, T.-P., Soliman, C., Redmond, S. J., Tappen, T., Kollmorgen, J., Geng, Q., Moody, D. B., Scriba, T. J., Uldrich, A. P., Minnaard, A. J., Seshadri, C., Venugopal, H., Shahine, A., Rossjohn, J., Godfrey, D. I., Gherardin, N. A.. 2026-06-22. Conserved T cell receptor usage underpins recognition of CD1c presenting a mycobacterial lipid. https://doi.org/10.64898/2026.06.17.733038

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