Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murine graft-versus-host disease: Regulatory role of donor CD8⁺ T cells

Acute and chronic graft-versus-host disease (GVHD) in the parent-into-F₁ model are mediated by predominantly cellular or humoral immune responses, respectively, and are strikingly different entities by 2 wk of disease. Both forms of GVHD, however, evolve from a common starting point, i.e., donor CD4⁺ T cell recognition of host alloantigen and IL-2 production. Our study examines the first 2 wk of GVHD to delineate the events that critically influence GVHD development. Surprisingly, both forms of GVHD are initially characterized by increased Th2 cytokine (IL-4 and IL-10) production and B cell activation which persists into wk 2. The earliest distinguishing features of acute GVHD were detectable at days 5 through 7 of disease and consisted of 1) expansion of donor CD8⁺ T cells, and 2) increased IFN-γ production by donor CD4⁺ and CD8⁺ T cells. Interestingly, IFN-γ production by donor CD4⁺ T cells was not seen if donor CD8⁺ T cells were not engrafted in comparable numbers. Chronic GVHD in the DBA-into-BDF₁ model was found to be caused by a relative defect in the ability of DBA CD8⁺ T cells to induce acute GVHD and to produce IFN-γ. These studies demonstrate that both acute and chronic GVHD begin as a Th2 cytokine-mediated, B cell stimulatory response. The transition to acute GVHD is critically dependent on the engraftment of donor CD8⁺ T cells, which terminate B cell hyperactivity by 1) eliminating activated B cells and 2) promoting IFN-γ secretion by donor CD4⁺ T cells.