CD8 T Cell Exhaustion in Human Visceral Leishmaniasis

Abstract

Little is known about CD8 T cells in human visceral leishmaniasis (VL) and it is unclear if these cells have a protective, pathological and/or suppressive function. In experimental VL CD8 T cells have been shown to contribute to parasite control and play an important role in vaccine-generated immunity. To better understand the role of CD8 T cells in human VL, we examined molecules associated with anergy and cytotoxic T lymphocytes (CTL) in peripheral blood mononuclear cells (PBMC) and splenic aspirates (SA), and in CD8 cells derived from these tissues. Gene and surface marker expression suggest that splenic CD8 cell predominantly display an anergic phenotype, whereas CD8-PBMC have features of both anergic cells and CTLs. CD8 cells contribute to the baseline IFNγ levels in whole blood (WB) and SA cultures, but not to the Leishmania induced IFNγ release that is revealed using WB cultures. Blockade of CTLA-4 or PD1 had no effect on IFNγ production or parasite survival in SA cultures. Following cure, CD8 T cells contribute to the Leishmania induced IFNγ production observed in Leishmania stimulated cell cultures. We suggest CD8 T cells are driven to anergy/exhaustion in human VL, which affect their ability to contribute to protective immune responses.

A Subset of Neutrophils Expressing Markers of Antigen-Presenting Cells in Human Visceral Leishmaniasis

“…Lymphoid cells in either the whole blood or the low-density PBMC fraction in subjects with VL express high levels of programmed cell death ligand-1 (PDL1) (Figure 6C), consistent with our prior observation of high PD1 expression on CD8 + T cells from patients with [22]. Furthermore, there was a significant increase in PDL1 expression on the surface of on LDGs from patients with VL ( Figure 6D).…”

Tumor necrosis factor alpha neutralization has no direct effect on parasite burden, but causes impaired IFN-γ production by spleen cells from human visceral leishmaniasis patients

“…Leishmania infected macrophages produces large amount of TNF-α [40] and this TNF-α can contribute to IFN-γ production by T cells and NK cells [41], so TNF-α blockade could interfere with IFN-γ secretion, as supported by our data. Neutralization of TNF-α has previously been reported to inhibit IFN-γ production by CD8 + T cells [42; 43], and we have also shown that CD8 + T cells contribute to endogenous IFN-γ production in SA cell cultures [44]. This suggest that TNF-α can induce exaggerated production of IFN-γ which induces tissue damage and pathology as seen in disease severity.…”

Evaluation of a biodegradable microparticulate polymer as a carrier for Burkholderia pseudomallei subunit vaccines in a mouse model of melioidosis

“…Splenocytes were stained for CD107a, CD8, CD3 and CD4 cell surface markers (Fischer Scientific) and flow cytometric acquisition and analysis was done using a BD FACS Caliber instrument (BD Biosciences, San Jose, CA). The de-granulation protocol was followed as described elsewhere (Gautam et al;Smith et al, 2009). The absolute change in CD107a expression produced by antigen re-stimulation was calculated by subtracting the value produced by unstimulated cells (baseline) from the value produced by lysatestimulated cells.…”