Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses

Abstract

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 [1][2][3] . 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 4,5 . 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.T reg cell deficiency results in activation and expansion of CD4 + and CD8 + T cells, dendritic cells, granulocytes and macrophages, and greatly increased production of a wide range of cytokines including interleukin (IL)-2, T H 1 and T H 2 cytokines 6,7 . Expression of Foxp3 is required for the establishment and maintenance of T reg lineage identity and suppressor function [8][9][10][11] . Our recent study suggested that in T reg cells Foxp3 might regulate expression of IRF4 (refs 12 -14) a transcription factor that is indispensable for T H 2 effector cell differentiation 15,16 . Furthermore, a recent study suggested a prominent role for IRF4 in T H 17Correspondence and requests for materials should be addressed to A.Y.R. (rudenska@mskcc.org). † Present address: Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.Supplementary Information is linked to the online version of the paper at www.nature.com/nature.Author Information Reprints and permissions information is available at www.nature.com/reprints. Full Methods and any associated references are available in the online version of the paper at www.nature.com/nature. Fig. 1a, b). Irf4 messenger RNA was increased in thymic and peripheral Foxp3 + T reg cells in comparison to CD25 − Foxp3 − CD4 + T cells (data not shown) 8 . Furthermore, Foxp3 knockdown using a retrovirally encoded Foxp3-specific short hairpin RNA resulted in a marked diminution in Irf4 mRNA ( Supplementary Fig. 1c 1...

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

“…However, it is not clear whether such Treg cells have intrinsically different suppressive function or whether they share common suppressive properties and the specificity is exerted mainly through local environmental adaptation. The latter hypothesis is supported by the observations that Treg cells isolated from these studies largely show intact suppressive activity in vitro (9)(10)(11)(12). We sought to approach this question by addressing whether transcriptionally diverse Treg cell subsets exist in humans, and whether the diversity accounts for potential differences in their in vitro functionality.…”

“…Several key studies have revealed a biased breakdown of tolerance when Treg cells are genetically mutated for particular genes. Specifically, Tregspecific deletion of T-bet, IFN regulatory factor 4, Stat3, and Bcl6 resulted in the impairment of specific regulation of Th1, Th2, Th17, and T follicular helper cells, respectively (9)(10)(11)(12). The finding that the key transcription factors for Th cell differentiation are also required for Treg cells to suppress these Teff cells suggests that the Treg population comprises multiple functional subsets, some of which may have a designated Th cell target.…”

FOXP3+ regulatory T cells and their functional regulation

“…17 On the other hand, the methylbinding domain protein Mbd2 works reversely on CNS2 methylation and plays an important role in promoting CNS2 demethylation and FOXP3 expression. 18 In humans, CD4 19,20 There is also substantial data that suggest how [21][22][23] Additionally, Jinfang Zhu and colleagues confirmed that Tbet 1 Treg cells were able to convert into GATA3 1 Treg cells, and vice versa, which suggests that Th subset-specific reprogramming is a dynamic process. 24 STABILITY AND PLASTICITY OF FOXP3 1 TREG CELLS The topic of Treg cell lineage stability and plasticity has been controversial for many years.…”

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

“…13,14 In addition, Treg-specific deletion of the transcription factors IRF4 (interferon regulatory factor 4) or STAT3 (signal transducer and activator of transcription 3) resulted in an impaired regulation of Th2-and Th17-dominated immune responses, respectively. 15,16 Recently, a population of germinal center-resident Tregs, termed follicular regulatory T cells, was identified. 17,18 These follicular regulatory T cells suppress germinal center B and T cells and depend, similar to their follicular T helper cell counterparts, on the expression of the transcription factor Bcl6 for their development.…”