Abstract

BackgroundMalaria, one of the largest health burdens worldwide, is caused by Plasmodium spp. infection. Upon infection, the host’s immune system begins to clear the parasites. However, Plasmodium species have evolved to escape the host’s immune clearance. T-cell immunoglobulin and mucin domain 3 (Tim-3), a surface molecule on most immune cells, is often referred to as an exhaustion marker. Galectin (Gal)-9 is a Tim-3 ligand and the T helper (Th) 1 cell response is inhibited when Gal-9 binds to Tim-3. In the present study, dynamic expression of Tim-3 on key populations of lymphocytes during infection periods of Plasmodium berghei and its significance in disease resistance and pathogenesis were explored.MethodsTim-3 expression on critical lymphocyte populations and the proportion of these cells, as well as the levels of cytokines in the sera of infected mice, were detected by flow cytometry. Further, in vitro anti-Tim-3 assay using an anti-Tim-3 antibody and in vivo Tim-3-Gal-9 signaling blockade assays using α-lactose (an antagonist of Gal-9) were conducted. An Annexin V Apoptosis Detection Kit with propidium iodide was used to detect apoptosis. In addition, proteins associated with apoptosis in lung and spleen tissues were confirmed by Western blotting assays.ResultsIncreased Tim-3 expression on splenic CD8+ and splenic CD4+, and circulatory CD4+ T cells was associated with a reduction in the proportion of these cells. Furthermore, the levels of interleukin (IL)-2, IL-4, IL-6, IL-22, and interferon (IFN)-γ, but not that of tumor necrosis factor alpha (TNF-α), IL-10, and IL-9, increased to their highest levels at day 4 post-infection and decreased thereafter. Blocking Tim-3 signaling in vitro inhibited lymphocyte apoptosis. Tim-3-Gal-9 signaling blockade in vivo did not protect the mice, but induced the expression of the immunosuppressive molecule, T cell immunoreceptor with Ig and ITIM domains (TIGIT), in Plasmodium berghei ANKA-infected mice.ConclusionsTim-3 on lymphocytes negatively regulates cell-mediated immunity against Plasmodium infection, and blocking Tim-3-galectin 9 signaling using α-lactose did not significantly protect the mice; however, it induced the compensatory expression of TIGIT. Further investigations are required to identify whether combined blockade of Tim-3 and TIGIT signaling could achieve a better protective effect.

Highlights

  • Malaria, one of the largest health burdens worldwide, is caused by Plasmodium spp. infection

  • Previous studies have found substantial levels of major histocompatibility (MHC) class I molecules expressed on erythroblasts before or after Plasmodium infection, and ­CD8+ T cells might target MHC I-positive parasitized erythroblasts and produce interferon gamma (IFN-γ) to clear the parasites [6]. ­CD4+ T cells, which are essential for balancing protection and pathology of hosts, are major producers of pro-inflammatory and regulatory cytokines [7]

  • T-cell immunoglobulin and mucin domain 3 (Tim-3) has been previously reported to play an important role in Plasmodium infection in human samples and C57BL/6 mice [20]

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Summary

Introduction

One of the largest health burdens worldwide, is caused by Plasmodium spp. infection. Previous studies have found substantial levels of major histocompatibility (MHC) class I molecules expressed on erythroblasts before or after Plasmodium infection, and ­CD8+ T cells might target MHC I-positive parasitized erythroblasts and produce interferon gamma (IFN-γ) to clear the parasites [6]. T follicular helper (TFH) cells (a subset of ­CD4+ T cells) release interleukin (IL)-21, which is a key to promoting effective germinal center formation and to activate protective, long-lasting B cell responses and humoral immune responses [8]. Other components, such as natural killer (NK) cells, γδT cells, and the host microbiota, are involved in the clearance of parasites, directly or indirectly [9]

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