Cytotoxic CD4+ T cells driven by T-cell intrinsic IL-18R/MyD88 signaling predominantly infiltrate Trypanosoma cruzi-infected hearts
- Rosalind Franklin University of Medicine and Science, United States
- Universidade Federal Fluminense, Brazil
- Universidade Federal do Rio de Janeiro (UFRJ), Brazil
- Universidade Federal de Minas Gerais, Brazil
Abstract
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 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.
Data availability
Transcriptome data was uploaded to GEO and is already publicly available with the GEO accession no. GSE57738
Article and author information
Author details
Carlos-Henrique D Barbosa
Ana-Carolina Oliveira
Funding
Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (CNE Award E-26/202.603/2019)
- Maria Bellio
Conselho Nacional de Desenvolvimento Científico e Tecnológico (PQ Award 312143/2018-4)
- Maria Bellio
Conselho Nacional de Desenvolvimento Científico e Tecnológico (INCT -V 465293/2014-0)
- Maria Bellio
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance Code 001)
- Maria Bellio
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mouse experiments were conducted in accordance with guidelines of the Animal Care and Use Committee of the Federal University of Rio de Janeiro (Comitê de Ética do Centro de Ciências da Saúde CEUA - CCS/UFRJ, license: IMPPG022).
Human subjects: All individuals included in this work were volunteers and treatment and clinical care were offered to all patients, as needed, despite their enrollment in this research project. All participants provided written informed consent for participation in the study. This cross-sectional study is part of an extended project evaluating biomarkers of cardiomyopathy development in Chagas disease, which has the approval of the National Committee of Ethics in Research (CONEP#195/2007) and are in accordance with the Declaration for Helsinki.
Copyright
© 2022, Barbosa et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cytotoxic CD4+ T cells driven by T-cell intrinsic IL-18R/MyD88 signaling predominantly infiltrate Trypanosoma cruzi-infected hearts
eLife 11:e74636.
https://doi.org/10.7554/eLife.74636
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