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Alloreactive Memory T Cells Are Responsible for the Persistence of Graft-versus-Host Disease¹

Departments of Medicine and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Graft-vs-host disease (GVHD) is caused by a donor T cell anti-host reaction that evolves over several weeks to months, suggesting a requirement for persistent alloreactive T cells. Using the C3H.SW anti-C57BL/6 (B6) mouse model of human GVHD directed against minor histocompatibility Ags, we found that donor CD8⁺ T cells secreting high levels of IFN- in GVHD B6 mice receiving C3H.SW naive CD8⁺ T cells peaked by day 14, declined by day 28 after transplantation, and persisted thereafter, corresponding to the kinetics of a memory T cell response. Donor CD8⁺ T cells recovered on day 42 after allogeneic bone marrow transplantation expressed the phenotype of CD44^highCD122^highCD25^low, were able to homeostatically survive in response to IL-2, IL-7, and IL-15 and rapidly proliferated upon restimulation with host dendritic cells. Both allogeneic effector memory (CD44^highCD62L^low) and central memory (CD44^highCD62L^high) CD8⁺ T cells were identified in B6 mice with ongoing GVHD, with effector memory CD8⁺ T cells as the dominant (>80%) population. Administration of these allogeneic memory CD8⁺ T cells into secondary B6 recipients caused virulent GVHD. A similar allogeneic memory CD4⁺ T cell population with the ability to mediate persistent GVHD was also identified in BALB/b mice receiving minor histocompatibility Ag-mismatched B6 T cell-replete bone marrow transplantation. These results indicate that allogeneic memory T cells are generated in vivo during GVH reactions and are able to cause GVHD, resulting in persistent host tissue injury. Thus, in vivo blockade of both alloreactive effector and memory T cell-mediated host tissue injury may prove to be valuable for GVHD prevention and treatment.

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