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      The regulation of immune tolerance by FOXP3

      research-article
      Author(s): 1 , 2 , 3
      Publication date (Electronic):
      Journal: Nature reviews. Immunology

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          Abstract

          The proper restraint of the destructive potential of the immune system is essential for maintaining health. Regulatory T (T reg) cells ensure immune homeostasis through their defining ability to suppress the activation and function of other leukocytes. The expression of the transcription factor forkhead box protein P3 (FOXP3) is a well-recognized characteristic of T reg cells, and FOXP3 is centrally involved in the establishment and maintenance of the T reg cell phenotype. In this Review, we summarize how the expression and activity of FOXP3 are regulated across multiple layers by diverse factors. The therapeutic implications of these topics for cancer and autoimmunity are also discussed.

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          Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses.

          Ye Zheng, Ashutosh Chaudhry, Arnold Kas … (2009)
          In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of T(H)1, T(H)2 or T(H)17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (T(reg)). T(reg) cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented T(H)1 and T(H)2 cytokine production. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets. Here we show that in mouse T(reg) cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for T(H)2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows T(reg) cells with the ability to suppress T(H)2 responses. Indeed, ablation of a conditional Irf4 allele in T(reg) cells resulted in selective dysregulation of T(H)2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking T(reg) cells. Our results indicate that T(reg) cells use components of the transcriptional machinery, promoting a particular type of effector CD4(+) T cell differentiation, to efficiently restrain the corresponding type of the immune response.
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            Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance.

            Xuefang Cao, Sheng Cai, Todd A Fehniger … (2007)
            Granzyme B is important for the ability of NK cells and CD8(+) T cells to kill their targets. However, we showed here that granzyme B-deficient mice clear both allogeneic and syngeneic tumor cell lines more efficiently than do wild-type (WT) mice. To determine whether regulatory T (Treg) cells utilize granzyme B to suppress immune responses against these tumors, we examined the expression and function of granzyme B in Treg cells. Granzyme B was not expressed in naive Treg cells but was highly expressed in 5%-30% of CD4(+)Foxp3(+) Treg cells in the tumor environment. Adoptive transfer of WT Treg cells, but not granzyme B- or perforin-deficient Treg cells, into granzyme B-deficient mice partially restored susceptibility to tumor growth; Treg cells derived from the tumor environment could induce NK and CD8(+) T cell death in a granzyme B- and perforin-dependent fashion. Granzyme B and perforin are therefore relevant for Treg cell-mediated suppression of tumor clearance in vivo.
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              Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells.

              Jun. Wang, Andreea Ioan-Facsinay, Ellen I H van der Voort … (2007)
              Foxp3 plays a key role in CD4+ CD25+ T(reg) cell function in mice and represents a specific marker for these cells. Despite the strong association between FOXP3 expression and regulatory function in fresh human T cells, little is known about the dynamics of endogenous FOXP3 expression and its relation to the suppressive function in activated human T cells. Here, we addressed the dynamics of FOXP3 expression during human CD4+ T cell activation by plate-bound anti-CD3 Ab as well as the relationship between its expression and regulatory function at the single-cell level. Our data show that FOXP3 is expressed in a high percentage of activated T cells after in vitro stimulation of human CD4+ CD25- cells. FOXP3 expression is strongly associated with hyporesponsiveness of activated T cells, but is not directly correlated with their suppressive capabilities, as we demonstrate that it is also expressed in activated nonsuppressive T cells. However, in this nonsuppressive T cell population, FOXP3 expression is transient, while it is stably expressed in activated T cells that do display suppressive function, and in natural CD4+ CD25++ T(reg) cells. These data indicate that expression of endogenous FOXP3, in humans, is not sufficient to induce regulatory T cell activity or to identify T(reg) cells.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101124169
                Journal ID (pubmed-jr-id): 27017
                Journal ID (nlm-ta): Nat Rev Immunol
                Journal ID (iso-abbrev): Nat. Rev. Immunol.
                Title: Nature reviews. Immunology
                ISSN (Print): 1474-1733
                ISSN (Electronic): 1474-1741
                Publication date Nihms-submitted: 23 January 2018
                Publication date (Electronic): 31 July 2017
                Publication date (Print): November 2017
                Publication date PMC-release: 01 February 2018
                Volume: 17
                Issue: 11
                Pages: 703-717
                Affiliations
                [1 ]Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China
                [2 ]Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA
                [3 ]Department of Oncology, Immunology and Hematopoiesis Division, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 401 North Broadway, Baltimore, Maryland 21287, USA
                Article
                Accession ID: PMC5793224 Pmcid ID: PMC5793224 Pmc-uid ID: 5793224 Manuscript ID: nihpa936105
                DOI: 10.1038/nri.2017.75
                PMC ID: 5793224
                PubMed ID: 28757603
                SO-VID: 42ca151b-4e82-4c8d-a973-8960d3fa49c0
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