Evolution of the V, D, and J gene segments used in the primate gammadelta T-cell receptor reveals a dichotomy of conservation and diversity.

γδ T cells are an immunological enigma in that both their function in the immune response and the molecular mechanisms behind their activation remain unclear. These cells predominate in the epithelia and can be rapidly activated to provide an array of responses. However, no homologous γδ T-cell populations have been identified between humans and mice, and our understanding of what these cells recognize as ligands is limited. Here we take an alternative approach to understanding human γδ T-cell ligand recognition by studying the evolutionary forces that have shaped the V, D, and J gene segments that are used during somatic rearrangement to generate the γδ T-cell receptor. We find that distinctly different forces have shaped the γ and δ loci. The Vδ and Jδ genes are highly conserved, some even through to mouse. In contrast, the γ-locus is split: the Vγ9, Vγ10, and Vγ11 genes represent the conserved region of the Vγ gene locus whereas the remaining Vγ genes have been evolving rapidly, such that orthology throughout the primate lineage is unclear. We have also analyzed the coding versus silent substitutions between species within the V and J gene segments and find a preference for coding substitutions in the complementarity determining region loops of many of the V gene segments. Our results provide a different perspective on investigating human γδ T-cell recognition, demonstrating that diversification at particular γδ gene loci has been favored during primate evolution, suggesting adaptation of particular V domains to a changing ligand environment.

The 2.5 Å structure of CD1c in complex with a mycobacterial lipid reveals an open groove ideally suited for diverse antigen presentation.

CD1 molecules function to present lipid-based antigens to T cells. Here we present the crystal structure of CD1c at 2.5 Å resolution, in complex with the pathogenic Mycobacterium tuberculosis antigen mannosyl-ß1-phosphomycoketide (MPM). CD1c accommodated MPM's methylated alkyl chain exclusively in the A' pocket, aided by a unique exit portal underneath the α1 helix. Most striking was an open F' pocket architecture lacking the closed cavity structure of other CD1 molecules, reminiscent of peptide binding grooves of classical major histocompatibility complex molecules. This feature, combined with tryptophan-fluorescence quenching during loading of a dodecameric lipopeptide antigen, provides a compelling model by which both the lipid and peptide moieties of the lipopeptide are involved in CD1c presentation of lipopeptides.