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Restoration of established systemic inflammation and autoimmunity by Foxp3+ regulatory T cells

Cellular & Molecular Immunology volume 19, pages 133–135 (2022)Cite this article

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Immune tolerance ensures the disease-free status of an individual by preventing the appearance of pathological conditions, such as autoimmune and inflammatory diseases. Among the various players implicated in the maintenance of immune tolerance, CD4+CD25+ regulatory T (Treg) cells that express the X-linked transcription factor Forkhead box P3 (Foxp3) play a major role. FoxP3 governs the functions of Treg cells. In fact, a deficiency in Treg cells due to mutations in FoxP3 leads to fatal autoimmune and inflammatory conditions in humans called immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome. Similar observations have also been made in mice, in which FoxP3 deficiency leads to autoimmune pathology and death early in life. In addition, various mutations in Treg-associated immunoregulatory molecules lead to inflammatory conditions [1].

Previous data generated in mice have demonstrated that Treg cells are capable of preventing autoimmune responses throughout the lifespan [2]. Other reports, however, show that the functions of Treg cells depend on the local microenvironment, target cells and intensity of inflammation [3, 4]. Thus, under established inflammatory conditions, inflammatory mediators render Treg cells nonfunctional or target immune cells become refractory to suppression by Treg cells [3]. Moreover, autoimmune diseases are polygenic and associated with several predisposing factors, including variants in the genes that control inflammation. Defective Treg cell functions might be a consequence of single-nucleotide polymorphisms rather than the inability of Treg cells to exert immunosuppressive activity. Of note, neutralization of inflammatory cytokines such as TNF-α in rheumatoid arthritis patients was shown to lead to the appearance of a new subset of Treg cells that controlled inflammation, while bona fide Treg cells remained defective [5]. Additionally, the efficacy of Treg cell-mediated suppression could differ among distinct categories of inflammatory immune responses. Although adoptive transfer of Treg cells has been performed in both experimental models and patients [6, 7], the transferred Treg cells may not reach the site of inflammation in sufficient numbers. In view of these variable genetic, environmental and inflammatory parameters, whether Treg cells are able to function in the context of established systemic inflammation and thus reverse fatal autoimmunity remains an unanswered question.

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Fig. 1: Foxp3-mediated Treg function in an established systemic inflammation and autoimmune condition.

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Authors and Affiliations

  1. Department of Biotechnology & Microbiology, School of Sciences, Noida International University-NIU, Gautam Budh Nagar-201 308, Noida, Uttar Pradesh, India

    Varun Kumar Sharma

  2. Department of Biological Sciences and Engineering, Indian Institute of Technology Palakkad, Palakkad, 678 623, India

    Jagadeesh Bayry

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VKS and JB performed the literature search and analyses and drafted the manuscript.

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Correspondence to Jagadeesh Bayry.

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Sharma, V.K., Bayry, J. Restoration of established systemic inflammation and autoimmunity by Foxp3+ regulatory T cells. Cell Mol Immunol 19, 133–135 (2022). https://doi.org/10.1038/s41423-021-00831-4

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