B7-H1 Blockade Increases Survival of Dysfunctional CD8 ⁺ T Cells and Confers Protection against Leishmania donovani Infections

Abstract

Experimental visceral leishmaniasis (VL) represents an exquisite model to study CD8 ⁺ T cell responses in a context of chronic inflammation and antigen persistence, since it is characterized by chronic infection in the spleen and CD8 ⁺ T cells are required for the development of protective immunity. However, antigen-specific CD8 ⁺ T cell responses in VL have so far not been studied, due to the absence of any defined Leishmania-specific CD8 ⁺ T cell epitopes. In this study, transgenic Leishmania donovani parasites expressing ovalbumin were used to characterize the development, function, and fate of Leishmania-specific CD8 ⁺ T cell responses. Here we show that L. donovani parasites evade CD8 ⁺ T cell responses by limiting their expansion and inducing functional exhaustion and cell death. Dysfunctional CD8 ⁺ T cells could be partially rescued by in vivo B7-H1 blockade, which increased CD8 ⁺ T cell survival but failed to restore cytokine production. Nevertheless, B7-H1 blockade significantly reduced the splenic parasite burden. These findings could be exploited for the design of new strategies for immunotherapeutic interventions against VL.

Author Summary

The protozoan parasite Leishmania donovani is the cause of visceral leishmaniasis, a chronic disease that currently affects 12 million people worldwide. We are interested in understanding the immune mechanisms that can control infection. Preliminary studies suggested that CD8 ⁺ T cells can kill parasites and limit disease; however, studying these important killer cells has been hindered, because we do not know what parasite molecules they recognize. To overcome this, we engineered parasites to express ovalbumin. Since many tools exist to track and measure immune cells targeted at ovalbumin, we can now track the specific CD8 ⁺ T cell responses that develop upon infection with Leishmania. We found that Leishmania initially induced CD8 ⁺ T cells to divide and produce molecules such as IFN-gamma that may help them to kill parasites. However, the CD8 ⁺ T cells rapidly lost their effector function and died off as infection progressed. More encouragingly, though, we were able to recover some CD8 ⁺ T cell function by blocking immune inhibitory molecules that are induced by parasite infection. The recovered T cells killed parasites and controlled infection. These results are important as they could be exploited for the design of new therapeutic vaccine strategies aimed at inducing protective CD8 ⁺ T cells.