Role of perforin in controlling B-cell hyperactivity and humoral autoimmunity

To determine the role of perforin-mediated cytotoxic T lymphocyte (CTL) eff ector function in immune regulation, we studied a well-characterized mouse model of graft-versus-host disease (GVHD). Induction of acute GVHD using pe rforin-deficient donor T cells (pfp --> F1) initially resulted in features of acute GVHD, e.g., engraftment of both donor CD4(+) and CD8(+) T cells, u pregulation of Fas and Fast, production of antihost CTL, and secretion of b oth Th1 and Th2 cytokines. Despite fully functional Fast activity, pfp dono r cells failed to totally eliminate host B cells, and, by 4 weeks of diseas e, cytokine production in pfp --> F1 mice had polarized to a Th2 response. Pfp --> F1 mice eventually developed features of chronic GVHD, such as incr eased numbers of B cells, persistence of donor CD4 T cells, autoantibody pr oduction, and lupuslike renal disease. We conclude that in the setting of B - and T-cell activation, perforin plays an important immunoregulatory role in the prevention of humoral autoimmunity through the elimination of both a utoreactive B cells and ag-specific T cells. Moreover, an ineffective initi al CTL response can evolve into a persistent antibody-mediated response and , with it, the potential for sustained humoral autoimmunity.