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.
Highlights
Antigen-specific CD8+ T cell responses are essential for protection and clearance of many microbial pathogens
CD8+ T cells recognize peptides which are presented in the context of major histocompatibility complex (MHC) class I via T cell receptor (TCR)
Duration, and contraction of OT-I CD8+T cell responses during Leishmania donovani infection To determine the extent and significance of bystander activation and distinguish it from antigen-specific responses, we first compared the expansion of adoptively transferred OT-I CD8+ T cells in mice infected with wild type (LV9) and Ovalbumintransgenic (PINK) Leishmania donovani parasites
Summary
Antigen-specific CD8+ T cell responses are essential for protection and clearance of many microbial pathogens. Rare naıve CD8+ T cells are activated in secondary lymphoid tissues following encounter with dendritic cells expressing peptide/MHCI complexes [1]. The magnitude of expansion largely depends on the amount of antigen and/or the number of the naıve precursors [6,7]. This robust proliferation is followed by a programmed contraction, which occurs independently of duration of infection, magnitude of expansion or antigen dose [7]. Memory cells show increased responsiveness and undergo dramatic clonal expansion after reencounter with the same antigen, and thereby confer protection [4,9]
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