Immunosuppressive Effect of CTLA-4 Blockade and Regulatory Role of CD8 T Cells in Th2-mediated Humoral Immune Responses

CTLA-4 is a negative regulator for T cell activation and plays an important role in down-regulating immune responses and the maintenance of peripheral tolerance. The effect of initial treatment with anti-CTLA-4 mAb on murine acute and chronic graft-versus-host diseases (GVHD) induced by transfer of either C57BL/6 or BALB/c splenocytes into F1 recipient mice has been investigated. The treatment with anti-CTLA-4 mAb exacerbated the lethality of acute GVHD. Surprisingly, in a chronic GVHD model, the similar treatment with anti -CTLA-4 mAb significantly reduced serum IgE and IL-4 expression and ameliorated the manifestation of chronic GVHD. Analysis of the splenic phenotype revealed that blockade of CTLA-4 greatly enhanced donor T cell expansion, especially within the CD8 subset. The transfer of CD8-depleted splenocytes did not exhibit the inhibitory effect by the anti-CTLA-4 mAb treatment, suggesting that CD8 T cells are required for an inhibitory effect of anti-CTLA-4 mAb. The regulatory roles of CD8 T cells and CTLA-4 pathway blockade in Th2-mediated immune responses were further confirmed by in vitro experi-ments using BALB/c T cell responses to allo-antigen. The immunosuppresive effect of CTLA-4 blockade and the regulatory function of CD8 T cells in Th2-mediated immune responses were demonstrated.