IDENTIFICATION OF HIGH POTENCY MICROBIAL AND SELF LIGANDS FOR A HUMANAUTOREACTIVE CLASS II-RESTRICTED T-CELL CLONE

CD4(+) class II-restricted T cells specific for self antigens are thou ght to be involved in the pathogenesis of most human autoimmune diseas es and molecular mimicry between foreign and self ligands has been imp licated as a possible mechanism for their activation. In this report w e introduce combinatorial peptide libraries as a powerful tool to iden tify cross-reactive Ligands for these T cells. The antigen recognition of a CD4(+) T cell clone (TCC) specific for myelin basic protein pept ide (MBP) (86-96) was dissected by the response to a set of 220 11-mer peptide sublibraries. Based on the results obtained with the librarie s for each position of the antigen, artificial peptides were found tha t induced proliferative responses at much lower concentrations than MB P(86-96). In addition stimulatory ligands derived from protein sequenc es of self and microbial proteins were identified, some of them even m ore potent agonists than MBP(86-96). These results indicate that: (ii) for at least some autoreactive CD4(+) T cells antigen recognition is highly degenerate; (b) the autoantigen used to establish the TCC repre sents only a suboptimal ligand for the TCC; (c) a completely random an d unbiased approach such as combinatorial Peptide libraries can decryp t the spectrum of stimulatory ligands for a T cell receptor (TCR).