T cells expressing multiple co‐inhibitory molecules in acute malaria are not exhausted but exert a suppressive function in mice
Johannes Brandi, Cari Lehmann, Lea‐Christina Kaminski, Julian Schulze zur Wiesch, Marylyn M. Addo, Michael Ramharter, Maria Sophia Mackroth, Thomas Jacobs, Mathias Riehn
Abstract
Abstract Overwhelming activation of T cells in acute malaria is associated with severe outcomes. Thus, counter‐regulation by anti‐inflammatory mechanisms is indispensable for an optimal resolution of disease. Using Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice, we performed a comprehensive analysis of co‐inhibitory molecules expressed on CD4 + and CD8 + T cells using an unbiased cluster analysis approach. We identified similar T cell clusters co‐expressing several co‐inhibitory molecules like programmed cell death protein 1 (PD‐1) and lymphocyte activation gene 3 (LAG‐3) in the CD4 + and the CD8 + T cell compartment. Interestingly, despite expressing co‐inhibitory molecules, which are associated with T cell exhaustion in chronic settings, these T cells were more functional compared to activated T cells that were negative for co‐inhibitory molecules. However, T cells expressing high levels of PD‐1 and LAG‐3 also conferred suppressive capacity and thus resembled type I regulatory T cells. To our knowledge, this is the first description of malaria‐induced CD8 + T cells with suppressive capacity. Importantly, we found an induction of T cells with a similar co‐inhibitory rich phenotype in Plasmodium falciparum ‐infected patients. In conclusion, we demonstrate that malaria‐induced T cells expressing co‐inhibitory molecules are not exhausted, but acquire additional suppressive capacity, which might represent an immune regulatory pathway to prevent further activation of T cells during acute malaria.