Injection of A/J splenocytes (H-2Dd, Mlsc) into unirradiated (A/J x CBA)F1 (BAF1) host mice (H-2Dd/k, Mlsd) results in an acute suppressive graft-vs.-host reaction (GVHR), characterized by immune dysfunction and appreciable donor cell engraftment; injection of the CBA/J parent (H-2Dk, Mlsd), which recognizes no Mls disparity in the host, results in little or no GVHR. Furthermore, the Mlsa-reactive V beta 6 and V beta 8.1 T cell subsets in A/J T cells expand significantly in the GVHR host. Finally, depletion of V beta 6+ and V beta 8.1+ from the A/J population abrogates the proliferative response to BAF1 in vitro and the development of GVHR in vivo. Thus, the response to Mls determinants can contribute to the generation of a GVHR.