We propose a novel role for interleukin (IL) 6 in inducing rapid spontaneous proliferation (SP) of naive CD8 + T cells, which is a crucial step in the differentiation of colitogenic CD8 + T cells. Homeostasis of T cells is regulated by two distinct modes of cell proliferation: major histocompatibility complex/antigen -driven rapid SP and IL-7/IL-15 -dependent slow homeostatic proliferation. Using our novel model of CD8 + T cell -dependent colitis, we found that SP of naive CD8 + T cells is essential for inducing pathogenic cytokine-producing effector T cells. The rapid SP was predominantly induced in mesenteric lymph nodes (LNs) but not in peripheral LNs under the infl uence of intestinal fl ora and IL-6. Indeed, this SP was markedly inhibited by treatment with anti -IL-6 receptor monoclonal antibody (IL-6R mAb) or antibiotic-induced fl ora depletion, but not by anti -IL-7R mAb and/or in IL-15 -defi cient conditions. Concomitantly with the inhibition of SP, anti -IL-6R mAb signifi cantly inhibited the induction of CD8 + T cell -dependent autoimmune colitis. Notably, the transfer of naive CD8 + T cells derived from IL-17 ؊ / ؊ mice did not induce autoimmune colitis. Thus, we conclude that IL-6 signaling is crucial for SP under lymphopenic conditions, which subsequently caused severe IL-17 -producing CD8 + T cell -mediated autoimmune colitis. We suggest that anti -IL-6R mAb may become a promising strategy for the therapy of colitis.

Macrophages respond to infection with pathogenic Yersinia species by activating MAPK- and NF-κB-signaling pathways. To counteract this response, Yersiniae secrete a protease (Yersinia outer protein J (YopJ)) that is delivered into macrophages, deactivates MAPK- and NF-κB-signaling pathways, and induces apoptosis. NF-κB promotes cell survival by up-regulating expression of several apoptosis inhibitor genes. Previous studies show that deactivation of the NF-κB pathway by YopJ is important for Yersinia-induced apoptosis. To determine whether deactivation of the NF-κB pathway is sufficient for Yersinia-induced apoptosis, two inhibitors of the NF-κB pathway, IκBα superrepressor or A20, were expressed in macrophages. Macrophages expressing these proteins were infected with Yersinia pseudotuberculosis strains that secrete functionally active or inactive forms of YopJ. Apoptosis levels were substantially higher (5- to 10-fold) when active YopJ was delivered into macrophages expressing IκBα superrepressor or A20, suggesting that deactivation of the NF-κB pathway is not sufficient for rapid Yersinia-induced apoptosis. When macrophages expressing A20 were treated with specific inhibitors of MAPKs, similar levels of apoptosis (within ∼2-fold) were observed when active or inactive YopJ were delivered during infection. These results suggest that MAPK and NF-κB pathways function together to up-regulate apoptosis inhibitor gene expression in macrophages in response to Yersinia infection and that YopJ deactivates both pathways to promote rapid apoptosis. In addition, treating macrophages with a proteasome inhibitor results in higher levels of infection-induced apoptosis than can be achieved by blocking NF-κB function alone, suggesting that proapoptotic proteins are stabilized when proteasome function is blocked in macrophages.