In a complete MHC mismatched allogeneic model of mouse bone marrow transplantation (BMT), naive CD4+ T cells from the C57BL/6 donor spleen combined with T cell depleted bone marrow cells induce graft versus host disease (GVHD) in lethally irradiated BALB/c hosts, leading to death within 10–20 days. This is characterized by acute injury to the large bowel with severe diarrhea. It has been reported that naive CD4+ CD62L hi CD44 lo T cells induce severe GVHD, but that effector memory CD4+ CD62Llo CD44hi T cells obtained from untreated normal donors do not induce GVHD in this model. We hypothesized that the poor GVHD-inducing capacity of effector memory cells from untreated donors may reflect their lack of previous exposure to host alloantigens. We tested this hypothesis by comparing the ability of effector memory T cells obtained from untreated donors and donors immunized to host alloantigens to induce GVHD. Donors were immunized by injecting 50 x106 host spleen cells i.p. and after one week with 10x 106 cells. We sorted naive (CD62Lhi CD44 lo) and effector memory (CD62LloCD44 hi) CD4+ T cell subsets from C57BL/6 donor mice four weeks after immunization, and compared their GVHD-inducing capacity to the same T cells subsets sorted from unimmunized C57BL/6 donors. We found that CD62Llo CD44hi cells from unimmunized donors failed to induce GVHD in 85% of the hosts over 100 days while CD62LloCD44hi cells from immunized donors caused progressive weight loss and death in 100% of hosts (p <0.001). Whereas naive CD4+ Tcells from unimmunized donors responded vigorously to host stimulator cells in the mixed leukocyte reaction (MLR), and accumulated rapidly in the lymph nodes and spleen of irradiated hosts, effector memory CD4+ T cells had markedly reduced activities in these assays. We are currently comparing the activity of memory CD4+ T cells from immunized and unimmunized donors in these assays. In conclusion, memory CD4+ T cells from donors immunized to host alloantigens are able to induce lethal GVHD, but memory cells from unimmunized donors were not. We are testing whether the increased potency of memory T cells from immunized donors is due to their increased reactivity to alloantigens and increased ability to accumulate in the host target tissues of GVHD.