IL-12 regulated checkpoints in the CD8+ T cell response to Toxoplasma gondii (P3340)

Abstract

Abstract We have previously shown that IL-12 is necessary for the differentiation of KLRG1+ IFN-γ producing CD8+ T effector cells during the immune response to Toxoplasma gondii. However, which key events during the activation, differentiation and mobilization of CD8+ T effector cells are critically regulated by IL-12 have not been identified. By tracking the dynamics of endogenous and adoptively transferred T. gondii-reactive CD8+ T cells, we were able to identify two key IL-12 dependent checkpoints. IL-12 is critical for the early diversification of CD8+ T cells into KLRG1+ IFN-γ-producing T effector cells, which occurs even prior to their initial proliferation. Unexpectedly, acquisition KLGR1 expression was accompanied by an attenuation of CXCR3 expression and this down regulation was IL-12 dependent. We postulate that this IL-12-driven reduction of CXCR3 expression may allow these mature KLRG1+ CD8+ T cells to outmigrate from secondary lymphoid organs. Failure to suppress CXCR3 may result in the retention of KLRG1+ CD8+ T effector cells in secondary lymphoid organs and underlie the deficit in effector cell numbers observed at the site of T. gondii infection in IL-12 p35-/- hosts. Our study reveals that IL-12 implements the early diversification of CTLs by both promoting and attenuating expression of key CD8+ T lymphocyte genes required for their effector function and mobilization.