T cell reactivity to alloantigens results from direct and indirect recognition of allogeneic MHC molecules and/or peptides. Although direct recognition is not self-MHC restricted, indirect recognition, the result of alloantigen processing and presentation by host APC, is restricted by the self (responder) MHC molecule to which the allopeptide has bound. We have studied the MHC restriction and TCR usage in T cell alloreactivity to a synthetic peptide corresponding to amino acid residues 21-42 of the DR beta 1*0101 molecule. T cell lines were developed by in vitro immunization of T cells from three responders carrying the DR beta 1*1101 allele with this peptide. In all three responders, reactivity to peptide 21-42 was restricted by the DR11 molecule. A limited usage of V beta genes was found in these T cell lines, all of which shared the expression of V beta 13.2. Because indirect recognition of allopeptide may play an important role in chronic, antibody-mediated allograft rejection, study of the TCR gene usage may contribute to the development of specific immunosuppression therapy.