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.

Marginal Zone B Cells Regulate Antigen-Specific T Cell Responses during Infection

“…We have previously shown that L. donovani induces defective CD8 T cell responses with limited expansion capacity (23). Interestingly, although most of the CD8 T cells during peak expansion are CD62L lo , they do not express other markers typically associated with effector cells, such as PD-1 (23), Fas (data not shown), or KLRG1, and the majority of the CD62L lo effectors are uncharacteristically highly positive for Bcl2 (data not shown).…”

“…All Abs unless specified were from BD Pharmingen. For intracellular staining, splenocytes were stimulated with the SIINFEKL peptide (Genosphere Biotechnologies) and IL-2 (Amgen) in the presence of brefeldin A (BD Pharmingen) for 4 h at 37˚C followed by surface staining for anti-CD45.2/1 and -CD8 (23). The cells were then fixed, permeabilized, and stained with either isotypes or anti-granzyme B-PE (Caltag), anti-IFN-gallophycocyanin, anti-IL-2-PE (BD Pharmingen), and anti-TNF-a-PECy7 (eBioscience).…”

“…Further, we reported that at the end of contraction, ∼70-80% of the OT-I T cells displayed a central memory cell (T CM )-like phenotype and 20-30% were effector cells (23). Hence we next characterized the phenotype of adoptively transferred OT-I T cells in mMT mice at two different time points: during clonal expansion (day 7) and at the end of contraction (day 13).…”

“…CD8 T cells are very important effector cells in the immune response to the protozoan parasite L. donovani, a causative agent of VL (22,23). However, we have previously reported that mice infected with L. donovani developed deficient parasite-specific CD8 T cell responses, characterized by limited clonal expansion and functional exhaustion during chronic disease (23). In this study, we demonstrate that marginal zone B cells (MZB) suppress Ag-specific CD8 and CD4 T cell responses during the early stages of VL.…”

T cells responding to Trypanosoma cruzi detected by membrane TNF‐α and CD154 in chagasic patients

“…Cytokine secretion can be limited by the T cell exhaustion state 12, 32 during chronic viral infections 33, 34, malignant tumors 35, and parasitic diseases 36. Chronic chagasic patients displayed dysfunctional T cell responses characterized by increased frequency of terminally differentiated cells, monofunctional antigen‐specific T cell responses and progressive attenuation of cytokine production 7, 10, 21, 37.…”