Role of Granzyme B in mucosal immune responses

Abstract

Abstract Granzyme B is a serine protease initially described in cell-mediated cytotoxicity. Recently, granzyme B has been found to be produced by non-cytotoxic cells, and elevated levels of granzyme B or cells expressing it have been implicated in many disease states. To investigate the role of granzyme B in mucosal immune responses, we utilized two models of intestinal inflammation: infection with Citrobacter rodentium, a colon-specific bacterium that induces intestinal inflammation in mice; and a T cell transfer model of colitis. Following infection, C. rodentium colonization was observed in the colon of both wt and grzB−/− animals at 14d post-infection. While wt mice displayed no overt signs of infection, severe weight loss as well as disease-associated changes in appearance and colon pathology were observed in grzB−/− mice at 10–14d post-infection. Similarly, adoptive transfer of grzB−/− CD4+CD45RBhi naïve effector T cells into rag2−/− recipients led to severe weight loss and disease-associated changes in appearance by 21d post-transfer, while rag2−/− recipients of wt CD4+CD45RBhi T cells were relatively unaffected at this early time point. Interestingly, disease in recipients of grzB−/− T cells corresponded with increased IL-17+ CD4+ T cells in the mesenteric lymph nodes and colon lamina propria relative to recipients that received wt T cells. These data suggest that granzyme B functions in a protective manner during intestinal inflammation, possibly playing a role in T cell differentiation by holding generation of IL-17-producing T cells in check.