A diverse lipid antigen-specific T cell receptor repertoire is clonally expanded during active tuberculosis

摘要

Human T cells that recognize lipid antigens presented by highly conserved CD1 proteins often express semi-invariant T cell receptors (TCRs), but the true diversity of lipid antigen-specific TCRs remains unknown. We use CD1b tetramers and high-throughput immunosequencing to analyze thousands of TCRs from ex vivo sorted or in vitro expanded T cells specific for the mycobacterial lipid antigen, glucose monomycolate (GMM). Our results reveal a surprisingly diverse repertoire resulting from editing of germline encoded gene rearrangements analogous to MHC-restricted TCRs. We used a distance-based metric (TCRdist) to show how this diverse TCR repertoire builds upon previously reported conserved motifs by including subject-specific TCRs. In a South African cohort, we show that TCRdist can identify clonal expansion of diverse GMM-specific TCRs and accurately distinguish patients with active tuberculosis from control subjects. These data suggest that the similar mechanisms govern the selection and expansion of peptide and lipid antigen-specific T cells despite the non-polymorphic nature of CD1.