By means of a novel technique for identification and isolation of MHC class II-restricted antigen-specific T cells, we describe here in non-transgenic BALB / c mice physiological positive selection of an oligoclonal population of T cells which recognizes both a self MHC-derived peptide (Ialpha52) and a bacterial homologoue (Hi15). The results support a model for self peptide-mediated generation of T cells which have specificity for microbial antigens through molecular mimicry. This mechanism may be a model for the ontogeny of a physiological T cell response to infectious agents. Loss of control of these circuits may be part of the inciting factors of autoimmunity.