TY - JOUR T1 - Unbiased definition of a shared T-cell receptor motif enables population-based studies of tuberculosis JF - bioRxiv DO - 10.1101/123174 SP - 123174 AU - W. S. DeWitt AU - K. K. Quan AU - D. Wilburn AU - A. Sherwood AU - M. Vignali AU - S. C. De Rosa AU - C. L. Day AU - T. J. Scriba AU - H. S. Robins AU - W. Swanson AU - R. O. Emerson AU - C. Seshadri Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/03/123174.abstract N2 - Peptide-specific T cells that are restricted by highly polymorphic major histocompatibility complex (MHC) proteins express diverse T-cell receptors (TCRs) that are rarely shared among unrelated individuals. T-cells can also recognize bacterial lipid antigens that bind the relatively non-polymorphic CD1 family of proteins. However, genetic variation in human CD1 genes and TCR diversity expressed by CD1-restricted T-cells have not been quantitatively determined. Here, we show that CD1B is nearly nucleotide-identical across all five continental ancestry groups, providing evidence for purifying selection during human evolution. We used CD1B tetramers loaded with a mycobacterial glycolipid antigen to isolate T-cells from four genetically unrelated South African adults and cataloged thousands of TCRs from in-vitro expanded T-cells using immunosequencing. We identified highly conserved motifs that were co-expressed as a functional heterodimer and significantly enriched among tetramer-positive T-cells sorted directly from peripheral blood. Finally, we show that frequencies of these TCR motifs are increased in the blood of patients with active tuberculosis compared to uninfected controls, a finding that is confirmed by ex-vivo frequencies of tetramer-positive T-cells determined by flow cytometry. These data provide a framework for unbiased definition of TCRs targeting lipid antigens, which can be tested for clinical associations independently of host genetic background.Brief Summary We used human genetics and immunosequencing to define a shared T-cell receptor motif that is specific for a mycobacterial lipid antigen and associated with tuberculosis independently of host genetic background. ER -