Regulatory T cells: immune suppression and beyond

Foxp3-expressing regulatory T cells (Tregs) were originally identified as critical in maintaining self-tolerance and immune homeostasis. The immunosuppressive functions of Tregs are widely acknowledged and have been extensively studied. Recent studies have revealed many diverse roles of Tregs in shaping the immune system and the inflammatory response. This review will discuss our efforts as well as the efforts of others towards understanding the multifaceted function of Tregs in immune regulation

GATA3: a master of many trades in immune regulation

GATA3 has conventionally been regarded as a transcription factor that drives the differentiation of T helper (Th) 2 cells. Increasing evidence points to function for GATA3 beyond controlling Th2 differentiation. GATA3 regulates T cell development, proliferation and maintenance. Furthermore, recent studies have demonstrated important roles for GATA3 in innate lymphoid cells. Thus GATA3 emerges as a factor with diverse functions in immune regulation, which are in some cases cell-type specific and in others shared by multiple cell types. Here I discuss recent discoveries and the current understanding of the functions of GATA3 in immune regulation

TGF-β and Regulatory T Cell in Immunity and Autoimmunity

The immune response is controlled by several inhibitory mechanisms. These mechanisms include regulatory T cells, which exist in multiple classes. Notable among these are Foxp3-expressing regulatory T cells (Treg), NKT cells, and Tr1 cells. Common to these mechanisms are inhibitory cytokines such as interleukin-10 and transforming growth factor-beta (TGF-β). TGF-β and Foxp3-expressing Treg cells are critical in maintaining self-tolerance and immune homeostasis

Chromatin remodeling complex in Treg function

Regulatory T cells (Treg), formerly known as suppressor T cells, are essential for maintaining self-tolerance as well as immune homeostasis. Lack of Treg or normal function of Treg often leads to lymphoproliferative syndrome and autoimmunity in human and mouse. The chromatin remodeling BAF complex regulates gene expression through the activity of Brg. Genetic ablation of Brg gene in mouse resulted in early embryonic lethality. T cell failed to develop in the thymus when Brg is deleted at DN stage. Using a Brg conditional KO mouse model, we deleted Brg at the DP stage in the thymus. Unexpectedly, T cells developed and matured normally. However, these mice displayed lympho-proliferative syndrome 2–4 months of age with enlarged peripheral lymphoid organs and leukocyte infiltration in non-lymphoid organs. T cells from these mice turned into effector cells producing increased amounts of effector cytokines as early as 4 weeks after birth. Further analysis revealed that the Treg population was specifically affected by Brg deletion. In this mini-review, we will discuss in detail the properties of Tregs controlled by Brg and the potential underlying mechanisms for an unanticipated, specific role of the Brg-containing BAF complex in controlling Treg functions

BPTF Is Essential for T Cell Homeostasis and Function

Bromodomain PHD Finger Transcription Factor (BPTF), a ubiquitously expressed ATP-dependent chromatin-remodeling factor, is critical for epigenetically regulating DNA accessibility and gene expression. While BPTF is important for the development of thymocytes, its function in mature T cells remains largely unknown. By specifically deleting BPTF from late DN3/DN4 stage of developing T cells, we found that BPTF was critical for the homeostasis of T cells via a cell intrinsic manner. In addition, BPTF was essential for the maintenance and function of Treg cells. Treg cell-specific BPTF deletion led to reduced Foxp3 expression, increased lymphocyte infiltration in the non-lymphoid organs and a systemic autoimmune syndrome. These findings therefore reveal a vital role for BPTF in T and Treg cell function and immune homeostasis

Proteomic dissection of LPS-inducible, PHF8-dependent secretome reveals novel roles of PHF8 in TLR4-induced acute inflammation and T cell proliferation

Endotoxin (LPS)-induced changes in histone lysine methylation contribute to the gene-specific transcription for control of inflammation. Still unidentified are the chromatin regulators that drive the transition from a transcriptional-repressive to a transcriptional-active chromatin state of pro-inflammatory genes. Here, using combined approaches to analyze LPS-induced changes in both gene-specific transcription and protein secretion to the extracellular compartment, we characterize novel functions of the lysine demethylase PHF8 as a pro-inflammatory, gene-specific chromatin regulator. First, in the LPS-induced, acute-inflamed macrophages, PHF8 knockdown led to both a reduction of pro-inflammatory factors and an increase in a transcriptional-repressive code (H3K9me2) written by the methyltransferase G9a. Through unbiased quantitative secretome screening we discovered that LPS induces the secretion of a cluster of PHF8-dependent, ‘tolerizable’ proteins that are related to diverse extracellular pathways/processes including those for the activation of adaptive immunity. Specifically, we determined that PHF8 promotes T-cell activation and proliferation, thus providing the first link between the epigenetic regulation of inflammation and adaptive immunity. Further, we found that, in the acute-inflamed macrophages, the acute-active PHF8 opposes the H3K9me1/2-writing activity of G9a to activate specific protein secretions that are suppressed by G9a in the endotoxin-tolerant cells, revealing the inflammatory-phenotypic chromatin drivers that regulate the gene-specific chromatin plasticity

An Essential Role of the Transcription Factor GATA-3 for the Function of Regulatory T Cells

Forkhead Box P3 (Foxp3)-expressing regulatory T (Treg) cells are central to maintaining self-tolerance and immune homeostasis. How Treg cell function and Foxp3 expression are regulated is an important question under intensive investigation. Here, we have demonstrated an essential role for the transcription factor GATA-3, a previously recognized Th2 cell master regulator, in controlling Treg cell function. Treg cell-specific GATA-3 deletion led to a spontaneous inflammatory disorder in mice. GATA-3-null Treg cells were defective in peripheral homeostasis and suppressive function, gained Th17 cell phenotypes and expressed reduced amounts of Foxp3. In addition, GATA-3 controlled Foxp3 expression by binding to and promoting the activity of cis-acting elements of Foxp3. Furthermore, the combined function of GATA-3 and Foxp3 was essential for Foxp3 expression. These findings provide insights into immune regulatory mechanisms and uncover a critical function of GATA-3 in Treg cells and immune tolerance

An Intrinsic Mechanism Predisposes Foxp3-Expressing Regulatory T Cells to Th2 Conversion In Vivo

Naturally occurring regulatory T (nTreg) cells express Foxp3 and were originally discovered as immune suppressors critical for self-tolerance and immune homeostasis. Through yet-to-be-defined mechanisms, nTreg cells were recently shown to convert into proinflammatory cells. Particularly, attenuation of Foxp3 expression led to Th2 conversion of nTreg cells in vivo. In this paper, we demonstrated an nTreg-specific mechanism controlling their Th2 conversion. We found that wild-type nTreg cells expressing reduced levels of Foxp3 but not those expressing no Foxp3 produced the Th2 cytokine IL-4. Intriguingly, IL-4 production by converted nTreg cells is required for Th2 differentiation of coexisting naive CD4 T cells in vivo, suggesting that Th2 conversion of nTreg cells might be critical for directing Th2 immune responses. Th2 conversion of nTreg cells was not due to their inability to become Th1 cells, because IFN-γ was produced by Foxp3-low–expressing cells when IL-4/STAT-6 signaling was abrogated. Surprisingly, however, unlike naive CD4 T cells whose IL-4 production is dependent on STAT-6, Foxp3-low–expressing cells generated IL-4 independent of STAT-6, indicating an intrinsic mechanism that favors nTreg-to-Th2 differentiation. Indeed, compared with naive CD4 T cells, nTreg expressed elevated levels of GATA-3 independent of STAT-6. And GATA-3 was required for nTreg-to-Th2 conversion. Foxp3 may account for this GATA-3 upregulation in nTreg cells, because ectopic expression of Foxp3 preferentially promoted GATA-3 but not T-bet expression. Thus, we have identified an intrinsic mechanism that imposes a Th2/Th1 imbalance and predisposes Foxp3-expressing cells to IL-4 production independent of STAT-6 signaling

An essential role for TAK1 in the contact hypersensitivity response

Contact hypersensitivity (CHS) is a delayed-type hypersensitivity that can be induced by haptens, such as 2,4-dinitrofluorobenzene (DNFB). Innate and adaptive immunities are both important for the development of CHS. To treat CHS-related diseases, such as allergic contact dermatitis, a disease prevalent in industrialized countries, ways of interfering with improper immune function during CHS responses need to be identified. Transforming growth factor-β-activated kinase-1 (TAK1), a member of mitogen-activated protein kinase kinase kinase family, is important for both innate and adaptive immunities. We thus hypothesized that the CHS response could be inhibited by interfering with TAK1 activity. Using a mouse model in which TAK1 deletion can be locally induced, we observed that TAK deficiency led to an impaired CHS response and was associated with defective T-cell expansion, activation and interferon (IFN)-γ production. In addition, we investigated the effect of deleting TAK1 specifically in dendritic cells (DC) on the CHS response. We found that when TAK1 is deficient in DC, the CHS response was abolished and hapten-elicited T-cell responses were defective. Collectively, this study demonstrates an essential role of TAK1 in the induction of CHS and suggests that targeting TAK1 could be a viable approach to treat CHS

Expression of Interleukin-10 in Intestinal Lymphocytes Detected by an Interleukin-10 Reporter Knockin tiger Mouse

SummaryTo identify interleukin-10 (IL-10)-producing cells in vivo, we generated a knockin mouse where an internal ribosome entry site (IRES) green fluorescence protein (GFP) element was inserted immediately before the polyadenylation site of the IL-10 gene. GFP fluorescence in cells from these mice was found to correlate positively with IL-10 protein expression. With this model, we found that after multiple T cell receptor (TCR) stimulations, strong expression of IL-10 was produced specifically by intraepithelial lymphocytes (IEL) in the small intestine and colonic lamina propria lymphocytes (cLPL). We found that anti-CD3 treatment induces T regulatory cell 1 (Tr1)-like cells in small intestinal IEL (sIEL) and led to the accumulation of naturally occurring regulatory T (nTreg) cells in colonic LPL (cLPL). These findings highlight the intestine as a unique site for induction of IL-10-producing T cells, which play a critical role in the regulation of inflammation in the gut