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Increasing attention has been directed to cytotoxic CD4 + T cells (CD4CTLs) in different pathologies, both in humans and mice. The impact of CD4CTLs in immunity and the mechanisms controlling their generation, however, remain poorly understood. Here, we show that CD4CTLs abundantly differentiate during mouse infection with the intracellular parasite Trypanosoma cruzi . CD4CTLs display parallel kinetics to Th1 cells in the spleen, mediate specific cytotoxicity against cells presenting pathogen-derived antigens and express immunoregulatory and/or exhaustion markers. We demonstrate that CD4CTL absolute numbers and activity are severely reduced in both Myd88 -/- and Il18ra -/- mice. Of note, the infection of mixed-bone marrow chimeras revealed that wild-type (WT) but not Myd88 -/- cells transcribe the CD4CTL gene signature and that Il18ra -/- and Myd88 -/- CD4 + T cells phenocopy each other. Moreover, adoptive transfer of WT CD4 + GzB + T cells to infected Il18ra -/- mice extended their survival. Importantly, cells expressing the CD4CTL phenotype predominate among CD4 + T cells infiltrating the infected mouse cardiac tissue and are increased in the blood of Chagas patients, in which the frequency of CD4CTLs correlates with the severity of cardiomyopathy. Our findings describe CD4CTLs as a major player in immunity to a relevant human pathogen and disclose T-cell intrinsic IL-18R/MyD88 signaling as a key pathway controlling the magnitude of the CD4CTL response., Competing Interests: CB, FC, AG, LB, JL, GM, AG, EN, WD, AO, AN, MB No competing interests declared, (© 2022, Barbosa, Canto, Gomes et al.)