Peptide Centric V beta Specific Germline Contacts Shape a Specialist T Cell Response

Certain CD8 T cell responses are particularly effective at controlling infection, as exemplified by elite control of HIV in individuals harboring HLA-B57. To understand the structural features that contribute to CD8 T cell elite control, we focused on a strongly protective CD8 T cell response directed against a parasite-derived peptide (HF10) presented by an atypical MHC-I molecule, H-2Ld. This response exhibits a focused TCR repertoire dominated by V beta 2, and a representative TCR (TG6) in complex with Ld-HF10 reveals an unusual structure in which both MHC and TCR contribute extensively to peptide specificity, along with a parallel footprint of TCR on its pMHC ligand. The parallel footprint is a common feature of V beta 2-containing TCRs and correlates with an unusual V alpha-V beta interface, CDR loop conformations, and V beta 2-specific germline contacts with peptides. V beta 2 and Ld may represent "specialist" components for antigen recognition that allows for particularly strong and focused T cell responses.