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abstracts
The T lymphocytes repertoire is divided into two major lineages, αβ and γδ T cells, which are defined by their T cell receptor (TCR) gene-segment usage. To date, the key discoveries on human CD1d restricted T cells have focussed on the type I Natural Killer T cells (NKT) subset that express an invariant TCR α chain (Vα24Jα18) which pairs with a β chain (Vβ11). The structural basis for the recognition of CD1d-lipid antigen by type I NKT cells is also now well established [1, 2]. However, there are other subsets of NKT cells that exhibit reactivity towards lipid-antigen presenting molecules (CD1d) but that do no express the typical Vα24Jα18 TCR. We identify human NKT cell subsets that express Vδ1+ γδ TCRs that recognize CD1d presenting the lipid-antigen α-galactosylceramide (α-Galcer). Here, we describe the first crystal structure of a CD1d/γδ TCR ternary complex [3] and provide structural insights into the binding mode of a γδ TCR with CD1d-αGalcer. The γδ TCR binds orthogonally over the A' pocket of CD1d, that is in clear contrast with the typical type I parallel docking mode in which the αβ TCR is perched over the F' pocket of CD1d. The germ line-encoded CDR1δ loop dominates the contacts with the CD1d molecule while the CDR3γ loop represents the main structural determinant for the antigen specificity. These findings highlight the emergence of diverse populations of NKT TCRs that exhibit different binding mode and lipid antigen specificity.
abstracts
Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease, characterized by inflammation of synovial tissue, joint pannus and bone erosion. The human leukocyte antigen (HLA) locus plays a vital role in immunity, encoding highly polymorphic molecules that present peptides to T cell lymphocytes. RA has a strong association with a region of the HLA-DRB1 locus known as the `shared epitope' (SE) and the presence of autoantibodies specific for citrullinated proteins. The SE maps to a highly polymorphic N-terminal region of the HLA-DRβ chain around amino acids 70-74. This region encodes a positively charged residue at position 71 that is thought to dictate the amino acid that is accommodated in the P4 pocket of the antigen-binding groove. Citrullination, the conversion of positively charged arginine to polar citrulline, is a physiological process catalyzed by peptidyl arginine deiminase. Previous studies have shown that citrullination of self-antigens can significantly increase the affinity of epitopes for SE alleles. Here we provide a molecular basis for how citrullinated vimentin and aggrecan epitopes can be presented by the SE alleles, HLA-DRB1*0401 and HLA-DRB1*0404. Citrulline was accommodated in the electropositive P4 pocket of HLA-DRB1*0401/04, whilst arginine was not. In addition, the RA resistant HLA-DRB1*0402 allomorph was capable of binding both arginine and citrulline in its electronegative P4 pocket. Peptide elution studies revealed that arginine was presented by HLA-DRB1*0402 but not by HLA-DRB1*0401/04. Moreover, citrullinated vimentin showed a greater sensitivity to proteolysis by cathepsin L, when compared to unmodified vimentin, indicating that citrullination can impact the repertoire of self-antigens presented. Using HLA Class II tetramers, we identified citrullinated vimentin and aggrecan specific CD4+ T cells from both HLA-DRB1*0401+ RA patients and healthy controls. In RA patients, the number of autoreactive T cells correlated with disease activity and were deficient in regulatory T cells compared to healthy controls. Together these findings provide significant insight into the role citrullination plays in the pathogenesis of RA[1].
