T-Cell Immunoglobulin- and Mucin-Domain-Containing Molecule 3 Signaling Blockade Improves Cell-Mediated Immunity Against Malaria.

Cell-mediated immune responses play important roles in immune protection against Plasmodium infection. However, impaired immunity, such as lymphocyte exhaustion, is a common phenomenon in malaria. T-cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) is an important regulatory molecule in cell-mediated immunity and has been implicated in malaria. In this study, it was found that Tim-3 expression on key populations of lymphocytes was significantly increased in both Plasmodium falciparum-infected patients and Plasmodium berghei ANKA (PbANKA)-infected C57BL/6 mice. Upregulation of Tim-3 led to lymphocyte exhaustion, while blocking Tim-3 signaling with an anti-Tim-3 antibody restored lymphocyte activity in Plasmodium infections. Further, anti-Tim-3 treatment accelerated the parasite clearance and relieved the symptoms of cerebral malaria in PbANKA-infected mice. In conclusion, Tim-3 on immune cells negatively regulates cell-mediated immunity against Plasmodium infection, and blocking Tim-3 signaling enhances sterile immunity and may play a protective role during malarial parasite infections.