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Background  Malaria, 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.    Methods  Tim-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.    Results  Increased 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.    Conclusions  Tim-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.

Tim-3 signaling blockade with α-lactose induces compensatory TIGIT expression in Plasmodium berghei ANKA-infected mice