CD137 functions mainly as a costimulatory molecule for T cell activation. However, its functions have been found in a variety of other immune and nonimmune cells and its immunoregulatory functions have also been revealing. In this study, we investigated the role of CD137 in the BM12-to-unirradiated, MHC II-mismatched C57BL/6 chronic graft-versus-host disease (GVHD) model. This lupus-like chronic GVHD occurs because donor CD4⁺ T cells break host B-cell tolerance with help from host CD4⁺ T cells. We found that chronic GVHD was inhibited when CD137^-/- mice were used as the host in this chronic GVHD model. Instead, they exhibited evident loss of body weight, lymphodepletion in the spleen, and intestinal and liver GVHD, characteristic features of acute GVHD. Consistent with these phenotype changes, there was progressive preferential differentiation of Th1 and Th17 cells in the spleen of CD137^-/- recipient mice. This pattern of helper T-cell differentiation was associated with replacement of splenic CD11b⁺ dendritic cells with CD8⁺ dendritic cells in CD137^-/- mice. Importantly, absence of CD137 signaling resulted in reduction in IDO-expressing B cells and FoxP3⁺ regulatory CD4⁺ T cells. These data indicate that CD137 signaling was critical in the generation of regulatory B cells and CD4⁺ T cells, without which donor T cells are activated, instead of entering into anergy, and attack host target tissues. Overall, our results suggest that host CD137 signaling is a key factor to determine the fate of donor CD4⁺ T cells during GVHD course.

CITATION INFORMATION: Cho H, Kim J, Kwon B, Lee J, Park K. Immunoregulatory Roles of CD137 Signaling in Graft-versus-Host Disease. Am J Transplant. 2017;17 (suppl 3).

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