CD40 signaling in CD8<SUP>+</SUP>CD40<SUP>+</SUP> T Cells turns on contra-T regulatory cell functions

CD4<SUP>+</SUP> regulatory T cells (Treg cells) mediate immunosuppression, whereas CD8<SUP>+</SUP> T cells confer resistance in many diseases. It is unknown whether CD8<SUP>+</SUP> T cells confer protection by antagonizing the Treg cells. Using a model of stage-specific immune responses against Leishmania donovani infection in susceptible BALB/c mice, we report that CD3<SUP>+</SUP>CD8<SUP>+</SUP>CD40<SUP>+</SUP> T cells executed CD40-dependent cytotoxicity on CD3<SUP>+</SUP>CD4<SUP>+</SUP>CD127dimGITR<SUP>+</SUP>CD25<SUP>+</SUP> Treg cells during the initial phase of the infection but were later apoptosed by IL-10. CD40 signaled through Ras, PI3K, and protein kinase C, resulting in p38MAPK- or ERK-1/2-independent, but NF-κ B-dependent, induction of the cytotoxic mediators granzyme and perforin. Adoptive transfer of CD3+CD8+CD40+ T cells reduced the L. donovani infection in BALB/c mice. These results identify CD3<SUP>+</SUP>CD8<SUP>+</SUP>CD40<SUP>+</SUP> T cells as the contra-Treg cells and imply a novel immunotherapeutic principle