RT Journal Article
SR Electronic
T1 Unbiased definition of a shared T-cell receptor motif enables population-based studies of tuberculosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 123174
DO 10.1101/123174
A1 W. S. DeWitt
A1 K. K. Quan
A1 D. Wilburn
A1 A. Sherwood
A1 M. Vignali
A1 S. C. De Rosa
A1 C. L. Day
A1 T. J. Scriba
A1 H. S. Robins
A1 W. Swanson
A1 R. O. Emerson
A1 C. Seshadri
YR 2017
UL http://biorxiv.org/content/early/2017/04/03/123174.abstract
AB 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.