A population of CD4hiCD38hi T cells correlates with disease severity in patients with acute malaria.

<b>Objective: </b>CD4⁺ T cells are critical mediators of immunity to <i>Plasmodium</i> spp. infection, but their characteristics during malarial episodes and immunopathology in naturally infected adults are poorly defined. Flow cytometric analysis of PBMCs from patients with either <i>P. falciparum</i> or <i>P. knowlesi</i> malaria revealed a pronounced population of CD4⁺ T cells co-expressing very high levels of CD4 and CD38 we have termed CD4^hiCD38^hi T cells. We set out to gain insight into the function of these novel cells.<br><br><b>Methods: </b>CD4⁺ T cells from 18 patients with <i>P. falciparum</i> or <i>P. knowlesi</i> malaria were assessed by flow cytometry and sorted into populations of CD4^hiCD38^hi or CD4^norm T cells. Gene expression in the sorted populations was assessed by qPCR and NanoString.<br><br><b>Results: </b>CD4^hiCD38^hi T cells expressed high levels of <i>CD4</i> mRNA and canonical type 1 regulatory T-cell (TR1) genes including <i>IL10</i>, <i>IFNG</i>, <i>LAG3</i> and <i>HAVCR2</i> (TIM3), and other genes with relevance to cell migration and immunomodulation. These cells increased in proportion to malaria disease severity and were absent after parasite clearance with antimalarials.<br><br><b>Conclusion: </b>In naturally infected adults with acute malaria, a prominent population of type 1 regulatory T cells arises that can be defined by high co-expression of CD4 and CD38 (CD4^hiCD38^hi) and that correlates with disease severity in patients with falciparum malaria. This study provides fundamental insights into T-cell biology, including the first evidence that CD4 expression is modulated at the mRNA level. These findings have important implications for understanding the balance between immunity and immunopathology during malaria.