Deficiencies of Inducible Costimulator (ICOS) During Chronic Infection with Upregulate the CD28-Dependent Cytotoxicity of CD8 T Cells and Their Effector Function Against Tissue Cysts of the Parasite.

We recently identified that the cerebral mRNA expression of inducible costimulator (ICOS) and its ligand, ICOSL, both significantly increase during the elimination of cysts from the brains of infected mice by the perforin-mediated cytotoxic activity of CD8 T cells. In the present study, we examined the role of ICOS in activating the effector activity of CD8 T cells in response to the presence of cysts in infected mice. Following the adoptive transfer of splenic CD8 T cells from chronically infected ICOS-deficient (ICOS) and wild-type (WT) mice to infected SCID mice, fewer CD8 T cells were detected in the brains of the recipients of ICOS CD8 T cells than the recipients of WT CD8 T cells. Interestingly, even with the lower migration rate of the ICOS CD8 T cells, those T cells eliminated cysts more efficiently than WT CD8 T cells did in the brains of the recipient mice. Consistently, the ICOS CD8 T cells secreted greater amounts of granzyme B in response to antigens in vitro than WT CD8 T cells did. We identified that CD8 T cells of infected ICOS mice express significantly greater levels of CD28 on their surface than CD8 T cells of infected WT mice, and the relative expression of CD28 mRNA to CD8β mRNA levels in the brains of the recipients of those CD8 T cells were strongly correlated with their relative expression levels of mRNA for T-bet transcription factors and perforin. Furthermore, blocking CD28 signaling using a combination of anti-CD80 and anti-CD86 antibodies eliminated the increased cytotoxic activity of the ICOS CD8 T cells in vitro. The present study uncovered notable compensatory interactions between ICOS and CD28, which protected the cytotoxic effector activity of CD8 T cells against microbial infection in a murine model of chronic infection with .