Although it is clear that positive selection of T cells involves recognition of specific self-peptide/MHC complexes, the nature of these self-ligands and their relationship to the cognate antigen are controversial. Here we used two complementary strategies to identify naturally occurring self-peptides able to induce positive selection of T cells bearing a specific T cell receptor, OT-I. Both the bioassay- and bioinformatics-based strategies identified the same self-peptides, derived from F-actin capping protein and β-catenin. These peptides displayed charge conservation at two key TCR contact residues. The biological activity of 43 other self-peptides and of complex peptide libraries directly correlated to the extent of conservation at TCR contact residues. These results demonstrate that selecting self-peptides are rare and can be identified by homology-based search strategies.
Bibliographical noteFunding Information:
The corresponding authors (S.V., K.A.H., and S.C.J.) all contributed equally to this work. We thank Tirza Doniger from the Research Computing Resource for writing the computer routines, Yuliang Ma for helpful discussions, John Hirst for FACS analysis, Andy Tomlinson for initial mass spectrometric analysis, and Kelly McCarthy for technical assistance. This collaborative work was supported by the NIH (AI41573 to S.V., AI39560 to K.A.H., and AI38903 to S.C.J.), NCI core support grant 5P30 CA16087, and NIH shared instrumentation (MALDI-TOF) grant 1 S10 RR14662 to T.A.N.