We studied whether allospecific CD4(+) effector memory T cells (T(EM)) could induce graft-versus-host disease (GVHD) using a novel GVHD model induced solely by CD4(+) T cell receptor transgenic TEa cells. Allospecific T(EM) generated in a lymphopenic host bore a typical memory phenotype. Moreover, these cells were able to elicit a faster and more effective proliferative response on challenge with alloantigen in vitro and to mediate "second-set" skin graft rejection in vivo. However, these allospecific T(EM) were unable to induce GVHD. Allospecific T(EM) recipients became tolerant to alloantigen as a result of clonal deletion. Even though allospecific T(EM) were able to respond to alloantigen initially, the expansion of these cells and inflammatory cytokine production during GVHD were dramatically decreased. The inability of allospecific T(EM) to sustain the alloresponse may be a result of enhanced activation-induced cell death. These observations provide insight into how allospecific CD4(+) T(EM) respond to alloantigen during GVHD and underscore the fundamental differences in alloresponses mediated by allospecific T(EM) in graft rejection and GVHD settings.