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The development of highly effective malaria vaccines and improvement of drug- treatment protocols to boost antiparasitic immunity are critical for malaria elimination. However, the rapid establishment of parasite-specific immune regulatory networks following exposure to malaria parasites hampers these efforts. Here, we identified stimulator of interferon genes (STING) as a critical mediator of type I interferon production by [CD4.sup.+] T cells during blood-stage Plasmodium falciparum infection. The activation of STING in [CD4.sup.+] T cells by cyclic guanosine monophosphate- adenosine monophosphate (cGAMP) stimulated IFNB gene transcription, which promoted development of IL-10- and IFN- [gamma]-coproducing [CD4.sup.+] T (type I regulatory [Tr1]) cells. The critical role for type I IFN signaling for Tr1 cell development was confirmed in vivo using a preclinical malaria model. [CD4.sup.+] T cell sensitivity to STING phosphorylation was increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. These findings identified STING expressed by [CD4.sup.+] T cells as an important mediator of type I IFN production and Tr1 cell development and activation during malaria., Introduction Malaria is a devastating human disease of global importance. It not only caused an estimated 247 million cases and 619,000 deaths in 2021, but also promoted poverty by imposing [...]

Control of intracellular parasites responsible for malaria requires host IFN-[[gamma].sup.+]T-[bet.sup.+][CD4.sup.+] T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory response. However, these IL-10-producing Th1 (induced type I regulatory [Tr1]) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10Th1 cells from IL-[10.sup.+]Tr1 cells in Plasmodium falciparum-infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P. berghei ANKA. We also identified a conserved Tr1 cell molecular signature shared between patients with malaria, dengue, and graft-versus-host disease. Genetic manipulation of primary human [CD4.sup.+] T cells showed that the transcription factor cMAF played an important role in the induction of IL-10, while BLIMP-1 promoted the development of human [CD4.sup.+] T cells expressing multiple coinhibitory receptors. We also describe heterogeneity of Tr1 cell coinhibitory receptor expression that has implications for targeting these molecules for clinical advantage during infection. Overall, this work provides insights into [CD4.sup.+] T cell development during malaria that offer opportunities for creation of strategies to modulate [CD4.sup.+] T cell functions and improve antiparasitic immunity., Introduction Under homeostatic conditions, inflammation is controlled by immunoregulatory networks that prevent disease (1). These networks comprise interactions among specialized immune cells, parenchymal cells, and tissue-specific microbiomes (2, 3). Following [...]