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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Microbial Immunology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1427055

The Divergent outcome of IL-4Rα signalling on Foxp3 T regulatory cells in listeriosis and tuberculosis

Provisionally accepted
Chia Julius Chia Julius 1Robert Rousseau Robert Rousseau 1Mumin Ozturk Mumin Ozturk 2Sibongiseni Poswayo Sibongiseni Poswayo 1Rodney Lucas Rodney Lucas 1Frank Brombacher Frank Brombacher 1Suraj P. Parihar Suraj P. Parihar 1*
  • 1 University of Cape Town, Cape Town, South Africa
  • 2 Radboud University Medical Centre, Nijmegen, Gelderland, Netherlands

The final, formatted version of the article will be published soon.

    Forkhead box P3 (Foxp3) T regulatory cells are critical in the maintenance of self-tolerance, immune homeostasis and regulation of the immune system. We investigated interleukin-4 receptor alpha (IL-4Rα) signalling on T regulatory cells (Tregs) in Listeria monocytogenes (Lm) infection using a mouse model in BALB/c background with IL-4Rα specifically knockdown on Tregs (Foxp3 cre IL-4Rα -/lox ). We showed an impairment of Treg responses, with a decreased bacterial burden and diminished tissue pathology in the liver and spleen, which translated into better survival. Mechanistically, we observed enhancement of Th1 signature with the characteristic T-bet transcriptional factor expression and increased effector T cells producing IFN-γ, IL-2 following ex-vivo stimulation with heat-killed Lm in Foxp3 cre IL-4Rα -/lox mice. Furthermore, CD8 T cells from Foxp3 cre IL-4Rα -/lox mice displayed increased cytotoxicity (Granzyme-B) with higher proliferation capacity (Ki-67), better survival (Bcl-2) with concomitant reduced apoptosis (activated caspase 3). In contrast to Lm, Foxp3 cre IL-4Rα -/lox mice displayed similar bacterial burdens, lung pathology and survival, despite increased T cell numbers and IFN-γ, TNF and IL-17 production during Mycobacterium tuberculosis (Mtb) infection. Our results demonstrated that the loss of IL-4Rα signalling on Foxp3 + T regulatory cells resulted in their functionality loss, which in turn led to survival benefit in listeriosis but not in tuberculosis. of Health under Award Number K43TW012587. The content is solely the responsibility of the authors and does not necessarily represent the views of the funders. The research was conducted in the BSL3 equipment platform supported by core funding from the Wellcome Trust (203135/Z/16/Z). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

    Keywords: Listeriosis, IL-4Rα, FoxP3 T cells, Mice, Tuberculosis

    Received: 02 May 2024; Accepted: 18 Sep 2024.

    Copyright: © 2024 Julius, Rousseau, Ozturk, Poswayo, Lucas, Brombacher and Parihar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Suraj P. Parihar, University of Cape Town, Cape Town, South Africa

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