Donor-unrestricted T cells in the human CD1 system

Abstract

The CD1 and MHC systems are specialized for lipid and peptide display, respectively. Here, we review evidence showing how cellular CD1a, CD1b, CD1c, and CD1d proteins capture and display many cellular lipids to T cell receptors (TCRs). Increasing evidence shows that CD1-reactive T cells operate outside two classical immunogenetic concepts derived from the MHC paradigm. First, because CD1 proteins are non-polymorphic in human populations, T cell responses are not restricted to the donor’s genetic background. Second, the simplified population genetics of CD1 antigen-presenting molecules can lead to simplified patterns of TCR usage. As contrasted with donor-restricted patterns of MHC-TCR interaction, the donor-unrestricted nature of CD1-TCR interactions raises the prospect that lipid agonists and antagonists of T cells could be developed.

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

“…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.…”

Targeting Innate-Like T Cells in Tuberculosis

“…As detailed below, the conserved genetic feature of each type of molecules is not restricted by the individual donor and will contribute to promiscuous tri-molecular interaction in a donor-unrestricted manner, providing an immunogenetic basis for explaining innate-like responses in unconventional T cells (91). …”

“…Similar to PRR molecules and drastically different from conventional HLA proteins, HLA class I-like proteins, such as MR1, CD1, and HLA-E, are considered to be highly conserved in humans (85, 91, 100, 101). Few SNPs have been identified by gene sequencing for HLA class I-like proteins, although more will likely be identified when human genome sequences are further available.…”

“…The MR1 ligand is located centrally within the MR1 ligand-binding cleft in a very small region, with the cyclic structure toward the base of the β-sheet and the ribityl side chain positioned upward, as shown in MR1 structure with ligand RL-6-Me-7-OH (Figures 2A,B). Interestingly, similar to ligand binding in CD1 proteins (19, 91), antigen binding to MR1 proteins exhibits very limited solvent accessibility and is largely buried within the MR1 protein. The interaction between RL-6-Me-7-OH and MR1 protein is dominated by hydrophobic interactions, with Tyr 7, Tyr 62, Trp 69, and Trp 156 forming an “aromatic cradle” that sequesters the ligand (Figures 2A,B) (31, 34).…”

“…However, most contacting sites from the TCRs of MAIT cells and lipid-specific T cells interact with the surface of MR1 or CD1 proteins rather than the antigens (Figures 2 and 4). Thus, in a very different manner, the TCRs of lipid-specific T cells use an asymmetric mode with little interference from associated lipid metabolites to dock on the surface of the CD1-lipid antigen complex as reviewed (91). Briefly, the lipid metabolites associated with CD1 proteins are either amphipathic or purely hydrophobic.…”