Minimal peptide length requirements for CD4(+) T cell clones - implications for molecular mimicry and T cell survival

CD4(+) T lymphocytes usually recognize peptides of 12-16 amino acids in the context of HLA class II molecules. We have recently used synthetic peptide combinatorial libraries to dissect in detail antigen recognition by autore active CD4(+) T cell clones (TCC). The results of these studies demonstrate d that antigen recognition by T cells is highly degenerate and that many cr oss-reactive ligands can be defined, some of which much more potent than th e selecting autoantigen. Based on these observations, we examined the respo nse of a myelin basic protein-specific HLA class II-restricted CD4(+) TCC t o truncation variants of optimal ligands, Surprisingly, pentapeptides, tetr apeptides and even tripeptides derived from different segments of the optim al ligands were recognized by the TCC, and some were even more potent than the selecting autoantigen. In addition, these peptides enhanced the surviva l of the TCC at low concentration. The relevance of this finding was suppor ted by the generation of pentapeptide-specific CD4(+) TCC from peripheral b lood lymphocytes. These observations not only change existing views on the length requirements for activation of CD4(+) HLA class Ii-restricted T cell s, but also extend our knowledge about the flexibility of TCR recognition a nd the potential for cross-reactivity in the immune system.