Abstract
T cells recognize mycobacterial glycolipid (mycolipid) antigens presented by CD1b molecules, but the role of CD4 and CD8 co-receptors in mycolipid recognition is unknown. Here we show CD1b-mycolipid tetramers reveal a hierarchy in which circulating T cells expressing CD4 or CD8 co-receptor stain with a higher tetramer mean fluorescence intensity than CD4-CD8- T cells. CD4+ primary T cells transduced with mycolipid-specific T cell receptors bind CD1b-mycolipid tetramer with a higher fluorescence intensity than CD8+ primary T cells. The presence of either CD4 or CD8 also decreases the threshold for interferon-γ secretion. Co-receptor expression increases surface expression of CD3ε, suggesting a mechanism for increased tetramer binding and activation. Targeted transcriptional profiling of mycolipid-specific T cells from individuals with active tuberculosis reveals canonical markers associated with cytotoxicity among CD8+ compared to CD4+ T cells. Thus, expression of co-receptors modulates T cell receptor avidity for mycobacterial lipids, leading to in vivo functional diversity during tuberculosis disease.
Highlights
T cells recognize mycobacterial glycolipid antigens presented by CD1b molecules, but the role of CD4 and CD8 co-receptors in mycolipid recognition is unknown
Invariant natural killer T cells recognize lipids presented by cluster of differentiation 1 (CD1) and mucosal-associated invariant T (MAIT) cells recognize metabolites presented by MHC-related protein 1 (MR1)[13,14]
We examine co-receptor expression on SGL-specific T cells directly ex vivo, as well as differences in SGL-CD1b and glucose monomycolate (GMM)-CD1b tetramer binding in ex vivo T cells, in vitro-derived T cell lines, and T cells transduced with an exogenous T cell receptor (TCR)
Summary
T cells recognize mycobacterial glycolipid (mycolipid) antigens presented by CD1b molecules, but the role of CD4 and CD8 co-receptors in mycolipid recognition is unknown. Peptide-specific T cells that express the CD8 co-receptor are traditionally cytotoxic T cells, which are defined by the expression of cytolytic effector molecules, such as granzymes and perforin[10]. These classifications are not absolute as T cells can exhibit functional plasticity and alter their functional program over time[11]. DN MAIT cells express less IFN-γ and more IL-17 than CD8 MAIT cells, and have a higher ROR-γt to T-bet ratio, indicative of a Th17 phenotype[21] These functional classes exist without two pathways for selection, antigen processing, and antigen presentation as in the case of MHC-I and MHC-II. Despite early reports that suggested these innate-like T cells might be limited to the minority of T cells lacking expression of co-receptors, iNKT and MAIT cells are clearly part of the majority of
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