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Immunol."],"abstract":"<jats:p>Activated cytotoxic CD8<jats:sup>+<\/jats:sup> T cells can selectively kill target cells in an antigen-specific manner. However, their prolonged activation often has detrimental effects on tissue homeostasis and function. Indeed, overwhelming cytotoxic activity of CD8<jats:sup>+<\/jats:sup> T cells can drive immunopathology, and therefore, the extent and duration of CD8<jats:sup>+<\/jats:sup> T cell effector function needs to be tightly regulated. One way to regulate CD8<jats:sup>+<\/jats:sup> T cell function is their suppression through engagement of co-inhibitory molecules to their cognate ligands (e.g., LAG-3, PD-1, TIM-3, TIGIT and CTLA-4). During chronic antigen exposure, the expression of co-inhibitory molecules is associated with a loss of T\u00a0cell function, termed T\u00a0cell exhaustion and blockade of co-inhibitory pathways often restores T cell function. We addressed the effect of co-inhibitory molecule expression on CD8<jats:sup>+<\/jats:sup> T\u00a0cell function during acute antigen exposure using experimental malaria. To this end, we infected OT-I mice with a transgenic <jats:italic>P. berghei<\/jats:italic> ANKA strain that expresses ovalbumin (PbTG), which enables the characterization of antigen-specific CD8<jats:sup>+<\/jats:sup> T cell responses. We then compared antigen-specific CD8<jats:sup>+<\/jats:sup> T cell populations expressing different levels of the co-inhibitory molecules. High expression of LAG-3 correlated with high expression of PD-1, TIGIT, TIM-3 and CTLA-4. Contrary to what has been described during chronic antigen exposure, antigen-specific CD8<jats:sup>+<\/jats:sup> T cells with the highest expression of LAG-3 appeared to be fully functional during acute malaria. We evaluated this by measuring IFN-\u03b3, Granzyme\u00a0B and Perforin production and confirmed the results by employing a newly developed T cell cytotoxicity assay. We found that LAG-3<jats:sup>high<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells are more cytotoxic than LAG-3<jats:sup>low<\/jats:sup> or activated but LAG-3<jats:sup>neg<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells. In conclusion, our data imply that expression of co-inhibitory molecules in acute malaria is not necessarily associated with functional exhaustion but may be associated with an overwhelming T cell activation. Taken together, our findings shed new light on the induction of co-inhibitory molecules during acute T cell activation with ramifications for immunomodulatory therapies targeting these molecules in acute infectious diseases.<\/jats:p>","DOI":"10.3389\/fimmu.2022.878320","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T09:16:55Z","timestamp":1657185415000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Increased Expression of Multiple Co-Inhibitory Molecules on Malaria-Induced CD8+ T Cells Are Associated With Increased Function Instead of 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