Abstract
Abstract Plasmodium infections and the disease malaria remain global health emergencies. CD4 T cells are essential for coordinating protective immunity against Plasmodium infection and promoting parasite clearance, yet long-lived immunity is rarely acquired. We have linked immune failures during human and experimental Plasmodium infection to the expression of immuno-regulatory networks that impair CD4 T cell activity. Here we show the immuno-inhibitory molecule, TIGIT, is highly expressed by parasite-specific CD4 T cells during human and experimental Plasmodium infection, but not experimental Toxoplasma gondii infection. Strikingly, the bulk (>90%) of TIGIT+ parasite-specific CD4 T cells are T-bet+ Th1 effectors, not Foxp3+ T regulatory cells. Moreover, sustained expression of TIGIT is associated with CD4 T cell-expression of IL-10 and is regulated by systemic inflammation, not persistent antigen or chronic T cell stimulation. Preliminary studies using TIGIT-specific agonistic and antagonistic reagents support the biological relevance of sustained TIGIT expression during Plasmodium infection. Current studies are focused on genetic manipulation of TIGIT to dissect the CD4 T cell subset-intrinsic roles of TIGIT during malaria. Collectively, our data support that TIGIT represents an additional host factor that can be targeted to improve immunity against Plasmodium infection and limit disease severity.
Published Version
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