Like many T cells in the myelin basic protein (MBP)-specific T-cell repertoire, CD4(-) GP2.3H3.16 (3H3) T cells recognize guinea pig MBP as an agonist but recognize autologous rat (R)MBP as a mixed agonist/antagonist. 3H3 T cells do not exhibit proliferative responses to RMBP but nonetheless respond to RMBP by accumulation of T-cell surface I-A/peptide complexes and generation of T-cell antigen-presenting cell (T-APC) activity. This study showed that presentation of RMBP by 3H3 T-APC is long-lived but is lost during interactions with cognate responders or on overt activation of T-APCs. Presentation of RMBP to encephalitogenic T cells resulted in the reciprocal activation of 3H3 T-APCs as evidenced by blastogenesis, proliferation, and induction of interleukin-2R and OX40 markers on 3H3 T-APC. These data indicate that T-APCs, like B-cell APCs, undergo clonal expansion after presentation of a cognate antigen to T-cell responders.