T cell receptor recognition of CD1b presenting a mycobacterial glycolipid

Abstract

CD1 proteins present microbial lipids to T cells. Germline-encoded mycolyl lipid-reactive (GEM) T cells with conserved αβ T cell receptors (TCRs) recognize CD1b presenting mycobacterial mycolates. As the molecular basis underpinning TCR recognition of CD1b remains unknown, here we determine the structure of a GEM TCR bound to CD1b presenting glucose-6-O-monomycolate (GMM). The GEM TCR docks centrally above CD1b, whereby the conserved TCR α-chain extensively contacts CD1b and GMM. Through mutagenesis and study of T cells from tuberculosis patients, we identify a consensus CD1b footprint of TCRs present among GEM T cells. Using both the TCR α- and β-chains as tweezers to surround and grip the glucose moiety of GMM, GEM TCRs create a highly specific mechanism for recognizing this mycobacterial glycolipid.

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

“…2E). Similar to a previous report (31), our results demonstrate the promiscuity of GEM18-TCR toward mycolate head group moieties. This suggests that meromycolate chain structure might be an antigenic determinant for GEM18-TCR activity.…”

“…On the other hand, GEM18-TCR differs from typical GMM-recognizing GEM-TCRs in that it possesses a Leu107α residue instead of Arg107α on its CDR3α loop, and Asp113β is absent, therefore GEM18-TCR lacks the stabilising 'tweezers' (31). The promiscuity toward different mycolate head groups suggests that GEM18-TCR recognises a common mycolate epitope that is shared between MA, GMM, and Gro-MM, likely mediated by Gly110α and Phe112α within the CDR3α loop (31). The observed weak GEM18-TCR responses toward GMM could have resulted through interference from the relatively bulky glucose moiety; however, we could not definitively rule out the processing of GMM to MA post cellular uptake.…”

“…TCRαβ + CD1b-restricted mycolate-specific GEM lymphocytes are a conserved T cell population in humans which expand upon Mtb infection and exhibit potent anti-mycobacterial effector functions through production of IFN-γ and TNF-α (9,31,37,38). Our demonstration of CD1b expression within human lung TB granulomas provides further evidence for lipid-specific T cell immunity in host defence against TB.…”

“…Structural studies of GEM42-TCR in complex with CD1b-GMM recently provided a molecular mechanism for GMM recognition by so called "typical" GMM specific GEM-TCRs such as GEM1, GEM21, and GEM42 (31). Arg107α on the CDR3α loop cooperates with Asp113β on the CDR3β loop forming a salt bridge that acts as a capstone, stabilising the alpha and beta 'tweezers' that grip the glucose head group moiety of GMM (31).…”

Four pathways of CD1 antigen presentation to T cells

“…However, recent studies hint that the spectrum of self lipids captured in cells is much more complex than previously thought [50], so the failure to identify motifs might simply result from insufficient sampling of the ligand repertoire. One type of size motif is established: CD1b captures foreign lipids that are much larger (C54-C82) than those found in association with other CD1 proteins [9,47,51,52]. However, comparatively large self lipids have not been detected, raising basic questions about endogenous ligands for CD1b.…”