Allosensitized Memory CD4 T Cells Induce Chronic Graft Versus Host Disease.

It has been reported that naive CD4⁺CD62L^hiCD44^lo T cells induce severe GVHD in a complete MHC mismatched allogeneic model of mouse bone marrow transplantation (BMT), but that effector memory CD4⁺CD62L^loCD44^hi T cells obtained from normal donors do not induce GVHD. The lack of GVHD-inducing capacity of effector memory cells from unprimed donors may reflect their lack of previous exposure to host alloantigens. We tested this hypothesis in a complete MHC mismatched allogeneic model of BMT by comparing the ability of effector memory T cells obtained from untreated C57BL/6 donors and donors immunized against host BALB/C alloantigens to induce GVHD. C57BL/6 donors were immunized by injecting 50 x10⁶ host BALB/C spleen cells i.p. and after one week with 10x 10⁶ cells. Both the unprimed and alloantigen primed CD4⁺ T cells expressed similar levels of lymph node homing chemokine receptor CCR7, and activation markers like CD69 and CD25. We sorted naive (CD62L^hiCD44^lo) and effector memory (CD62L^loCD44^hi) CD4⁺ T cell subsets from C57BL/6 donor mice four weeks after immunization, and compared their alloreactivity to BALB/C in an in vitro MLR. Interestingly effector memory CD4⁺ T cells from primed mice produced significantly higher levels of IFN_γ compared to the effector memory from unprimed donors. We found that CD62L^loCD44^hi cells from unimmunized donors failed to induce GVHD in 85% of the hosts over 100 days while CD62L^loCD44^hi cells from immunized donors caused progressive weight loss and death in 100% of hosts (p <0.001). Whereas naive CD4⁺ T cells from unimmunized donors accumulated rapidly in the lymph nodes and spleen of irradiated hosts, effector memory CD4⁺ T cells had markedly reduced accumulation in these tissues. Furthermore, at day 6 after transplantation effector memory CD4⁺ T cells from primed mice, showed hundred fold higher accumulation in the host liver compared to unprimed effector memory donor CD4⁺ T cells. Long term surviving hosts transplanted with primed effector memory cells showed histopathological features of chronic GVHD in liver characterized by portal tract inflammation and lymphocyte infiltration with bile duct injury. In conclusion, memory CD4⁺ T cells from donors immunized to host alloantigens are able to induce chronic GVHD , but memory cells from unimmunized donors do not.