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The Foxp3+ regulatory T cell population requires IL-4Rα signaling to control inflammation during helminth infections


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Nada Abdel Aziz1,2,3, Justin Komguep Nono1,2,4, Thabo Mpotje1,2, and Frank

Brombacher1,2,5

1 Cytokines and Diseases Group, International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa, 2 University of Cape Town, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa, 3 Biotechnology/Biomolecular Chemistry Program, Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt, 4 The Medical Research Centre, Institute of Medical Research and Medicinal Plant Studies (IMPM), Ministry of Scientific Research and Innovation, Yaoundé, Cameroon, 5 Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa

Introduction: Foxp3+ regulatory T cell (Treg) function is controlled by environmental cues of which cytokine-mediated signaling is a dominant component. In vivo, Interleukin-4-mediated signaling via Interleukin-4 receptor alpha (IL-4Rα) mediates Treg transdifferentiation into ex-Foxp3 Th2 or Th17 cells. Puzzlingly, however, IL-4-mediated signaling also reinforces the Foxp3 Treg compartment in vitro. In the face of such a conundrum, the present work was set forth to conclusively decipher the bases of the regulation of Foxp3+ Treg by IL-4Rα-mediated signaling.

Methodology: we have successfully generated and characterized a novel Foxp3+ specific IL-4Rα-deficient mouse model (Foxp3cre IL-4Rα-/lox). We have checked the role of IL-4Rα on Foxp3+ Tregs under steady-state and inflammatory conditions; Schistosoma mansoni and Nippostrongylus brasiliensis infections. Immune and histopathological responses were investigated by Immunohistochemistry, FACS and ELISA.

Results: By employing our mouse model where IL-4Rα-mediated signaling was specifically impaired within Foxp3+ Tregs, we demonstrated that deletion of IL-4Rα specifically within the Foxp3+ Tregs led to an exacerbation of immune effector responses with aggravated tissue pathology in tissue-dwelling helminth infections (S. mansoni or N. brasiliensis). Mechanistically, IL-4Rα deletion led to a reduced expression of Foxp3 and an impaired accumulation of Foxp3+ Tregs to inflamed tissues. In-depth cellular typing by flow cytometry revealed that the impairment of IL-4Rα-mediated signaling during helminth infections decreased the ability of central Tregs to convert into effector Tregs (eTregs) and caused a significant downregulation of markers associated with Treg migration (CXCR3) and accumulation in inflamed tissues (GATA3) as well as survival (Bcl-2).

Discussion and Conclusion: Complementing our past knowledge on a widely reported role for IL-4Rα signaling in the negative regulation and transdifferentiation of Foxp3+ Tregs in vivo, our present findings unprecedentedly uncover the host requirement for IL-4Rα mediated signaling on Foxp3+ Tregs to optimally control inflammation during helminth infections.





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