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Leon, Luis

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Leon, Luis

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    CD1b Tetramers Bind \(\alpha \beta\) T Cell Receptors to Identify a Mycobacterial Glycolipid-Reactive T Cell Repertoire in Humans
    (The Rockefeller University Press, 2011) Cheng, Tan-Yun; Turner, Marie; Seshadri, Chetan; Schiefner, Andre; Kalathur, Ravi C.; Annand, John W.; de Jong, Annemieke; Shires, John; Wilson, Ian A.; Altman, John D.; Kasmar, Anne G.; Van Rhijn, Ildiko; Leon, Luis; Brenner, Michael; Moody, David
    Microbial lipids activate T cells by binding directly to CD1 and T cell receptors (TCRs) or by indirect effects on antigen-presenting cells involving induction of lipid autoantigens, CD1 transcription, or cytokine release. To distinguish among direct and indirect mechanisms, we developed fluorescent human CD1b tetramers and measured T cell staining. CD1b tetramer staining of T cells requires glucose monomycolate (GMM) antigens, is specific for TCR structure, and is blocked by a recombinant clonotypic TCR comprised of TRAV17 and TRBV4-1, proving that CD1b-glycolipid complexes bind the TCR. GMM-loaded tetramers brightly stain a small subpopulation of blood-derived cells from humans infected with Mycobacterium tuberculosis, providing direct detection of a CD1b-reactive T cell repertoire. Polyclonal T cells from patients sorted with tetramers are activated by GMM antigens presented by CD1b. Whereas prior studies emphasized CD8\(^+\) and CD4\(^-\)CD8\(^-\) CD1b-restricted clones, CD1b tetramer-based studies show that nearly all cells express the CD4 co-receptor. These findings prove a cognate mechanism whereby CD1b-glycolipid complexes bind to TCRs. CD1b tetramers detect a natural CD1b-restricted T cell repertoire ex vivo with unexpected features, opening a new investigative path to study the human CD1 system.