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

Front Immunol. 2024 Oct 17:15:1427055. doi: 10.3389/fimmu.2024.1427055. eCollection 2024.

Abstract

Introduction: Forkhead box P3 (Foxp3) T regulatory cells are critical for maintaining self-tolerance, immune homeostasis, and regulating the immune system.

Methods: We investigated interleukin-4 receptor alpha (IL-4Rα) signalling on T regulatory cells (Tregs) during Listeria monocytogenes (L. monocytogenes) infection using a mouse model on a BALB/c background, specifically with IL-4Rα knockdown in Tregs (Foxp3creIL-4Rα-/lox).

Results: We showed an impairment of Treg responses, along with a decreased bacterial burden and diminished tissue pathology in the liver and spleen, which translated into better survival. Mechanistically, we observed an enhancement of the Th1 signature, characterised by increased expression of the T-bet transcription factor and a greater number of effector T cells producing IFN-γ, IL-2 following ex-vivo stimulation with heat-killed L. monocytogenes in Foxp3creIL-4Rα-/lox mice. Furthermore, CD8 T cells from Foxp3creIL-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 L. monocytogenes, Foxp3creIL-4Rα-/lox mice displayed similar bacterial burdens, lung pathology and survival during Mycobacterium tuberculosis (M. tuberculosis) infection, despite increased T cell numbers and IFN-γ, TNF and IL-17 production.

Conclusion: Our results demonstrated that the diminished IL-4Rα signalling on Foxp3+ T regulatory cells resulted in a loss of their functionality, leading to survival benefits in listeriosis but not in tuberculosis.

Keywords: Foxp3 T cells; IL-4Rα; listeriosis; mice; tuberculosis.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Forkhead Transcription Factors* / metabolism
  • Listeria monocytogenes* / immunology
  • Listeriosis* / immunology
  • Listeriosis* / microbiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mycobacterium tuberculosis / immunology
  • Signal Transduction*
  • T-Lymphocytes, Regulatory* / immunology
  • Tuberculosis* / immunology
  • Tuberculosis* / microbiology

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Il4ra protein, mouse

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by the ICGEB Arturo Falaschi predoctoral fellowship to JC, as well as funding from National Research Funding (NRF) South Africa and the South African Research Chair Initiative (SARChi) to FB. SPP is supported by the NRF Research Development Grants for Y-Rated Researchers (RDYR180413320675), NRF Incentive Funding for Rated Researchers (IFR180305315866), the South African Medical Research Council (SAMRC) Self-Initiated Research Grant, the Centre for Infectious Disease Research in Africa (CIDRI-Africa), and the Fogarty International Centre of the National Institutes 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.