Interestingly, single-cell heterogeneity in the transcriptional profile of effector CD4 + T cells, dictated in a microbe-specific manner, has been recently found in the gut ( Kiner et al., 2021). Different pathogen-derived molecular patterns (PAMPs) elicit distinct innate immune pathways, resulting in tailored Th responses against the infectious agent ( Kara et al., 2014). The role of CD4CTLs in immunity against intracellular parasites and the mechanisms operating in the generation and maintenance of this cell subset are poorly understood.įollowing the recognition of the cognate antigen-MHC complex and under the influence of cytokines secreted by antigen presenting cells (APCs), naïve CD4 + T cells proliferate and differentiate into diverse subsets, including Tfh, Th1, Th2, or Th17, with varied effector functions. At present, however, there are few studies on the CD4CTL response to infection with non-viral intracellular pathogens ( Burel et al., 2016 Canaday et al., 2001 Kotov et al., 2018 Krueger et al., 2021). Although more frequently found in chronic conditions, CD4CTLs have also been described during acute viral infection ( Brien et al., 2008 Brown et al., 2012 Fang et al., 2012 Jellison et al., 2005 Wilkinson et al., 2012). Editor's evaluationĬytotoxic CD4 + T cells (CD4CTLs) are present in viral infections, cancer and autoimmune diseases ( Cheroutre and Husain, 2013 Juno et al., 2017 Takeuchi and Saito, 2017). 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. 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. Moreover, adoptive transfer of WT CD4 +GzB + T cells to infected Il18ra -/- mice extended their survival. 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. We demonstrate that CD4CTL absolute numbers and activity are severely reduced in both Myd88 -/- and Il18ra -/- mice. 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. Here, we show that CD4CTLs abundantly differentiate during mouse infection with the intracellular parasite Trypanosoma cruzi. The impact of CD4CTLs in immunity and the mechanisms controlling their generation, however, remain poorly understood. Increasing attention has been directed to cytotoxic CD4 + T cells (CD4CTLs) in different pathologies, both in humans and mice.
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