The role of the transcription factor Foxp3 in the development of regulatory T cells

Kim, Jeong M.; Rudensky, Alexander Y.

doi:10.1111/j.0105-2896.2006.00426.x

Cited by 161 publications

(145 citation statements)

References 74 publications

(102 reference statements)

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“…We observed increased basal phosphorylation of Erk1/2 and c-Cbl in nTreg from WT and CD5 À/À mice, compared with naïve T cells, respectively, confirming the fact that nTreg must have been selected under conditions of high avidity [46]. When we compared WT to CD5 À/À mice (in which TCRmediated signals are presumably further enhanced), we detected increased levels of p-Erk in CD5 À/À Treg, compared with WT Treg, while phosphorylation of PI3K and Akt was only enhanced in naïve CD5 À/À thymocytes compared with naïve WT thymocytes.…”

Section: Discussionsupporting

confidence: 69%

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Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

et al. 2009

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It has been suggested that high affinity/avidity interactions are required for the thymic selection of Treg. Here, we investigated the role of CD5, a negative regulator of TCR signaling, in the selection and function of ''naturally occurring'' CD4 1 CD25 1 Treg (nTreg). Analysis of CD5 À/À mice showed a significant increase in the percentage and absolute numbers of CD4 1 CD25 1 Foxp3 1 thymocytes and peripheral T lymphocytes, compared with BALB/c mice. Thymi from CD5 À/À mice showed reduced cellularity due to increased apoptosis, which preferentially affected naïve T cells. To characterize nTreg selection at the molecular level we investigated the phosphorylation of Erk, c-Cbl, PI3K and Akt. CD5 À/À nTreg showed increased basal levels of p-Erk compared with wild-type nTreg. Interestingly, in response to CD3 plus CD28 costimulation, CD5 À/À naïve T cells but not CD5 À/À nTreg showed lower levels of p-Akt. Finally, CD5 À/À nTreg were thymus-derived and fully functional. We conclude that the enrichment of nTreg observed in the absence of CD5 signaling is due to de novo generation of nTreg and selective reduction of CD4 1 CD25 À naïve thymocytes. Furthermore, we provide new evidence supporting a potential role of CD5 in thymocyte survival, through a mechanism that may involve the phosphorylation of Akt.Key words: CD5 . Development . Treg . Signaling . Thymocyte IntroductionThe maintenance of immunological self-tolerance is a fundamental property of the immune system besides the clearance of pathogenic agents. Central and peripheral mechanisms exist to ensure the elimination or inactivation of potentially harmful autoreactive T cells. Negative selection in the thymus induces the deletion of most self-reactive T-cell clones during T-cell development [1]. However, some autoreactive T cells escape from clonal deletion and need to be controlled by peripheral mechanisms including peripheral T-cell deletion by activation-induced cell death [2], T-cell anergy [3] and T-cell-mediated suppression [4].Recently, non-deletional mechanisms of central tolerance have been re-evaluated, such as the development of thymus-derived Treg [5]. These cells are currently known as ''naturally occurring'' CD4 1 CD25 1 Treg (nTreg), which represent a small population (5-10%) of peripheral CD4 1 T cells and are characterized by high levels of surface CD25 and by the expression of Foxp3, a transcription factor, identified as a key regulator of nTreg development and function [6]. In addition, nTreg also express activation markers such 2233as CTLA-4, glucocorticoid-induced tumor necrosis factor receptor (GITR), CD62L, OX40 and CD103 [7,8]. nTreg were first studied for their role in maintaining self-tolerance [9], preventing autoimmune diseases [10] and the development of harmful immunopathological responses [11]. However, nTreg can also participate in modulating adaptive immunity to viruses, bacteria and parasites affecting favorably or detrimentally the outcome of immune responses to infections [12,13].The mechanisms of suppression used by Treg...

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Section: Discussionsupporting

confidence: 69%

“…Since selection of nTreg appear to require high affinity/avidity interactions [46], we hypothesized that CD5 might be involved in their generation. Here, we describe that the absence of CD5 leads to increased numbers of thymic and peripheral nTreg, accompanied by increased cell death of naïve thymocytes.…”

Section: Introductionmentioning

confidence: 99%

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

et al. 2009

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“…Experimental evidence supports the hypothesis that regulatory T cells (Tregs) are delineated into two subsets (6). ''Natural'' CD4 ϩ CD25 ϩ T cells emerge from the thymus as a distinct lineage (7)(8)(9), whereas ''adaptive'' CD4 ϩ CD25 ϩ Tregs are induced at the periphery from CD4 ϩ CD25 Ϫ T cells under particular conditions, i.e., antigenic stimulation and the presence of a cytokine environment (10)(11)(12)(13)(14). Most studies focused on brightly stained CD25 ϩ T cells (CD25 high ) considering that they included the majority of Tregs, whereas CD25 low T cells did not suppress and preferentially included activated T lymphocytes (15)(16)(17).…”

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confidence: 83%

Adaptive TGF-β-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment

You

Leforban

Garcia

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Previous results have shown that CD4 ؉ CD25 ؉ regulatory T cells (Tregs) control autoimmunity in a spontaneous model of type 1 diabetes, the nonobese diabetic (NOD) mouse. Moreover, anti-CD3 reverses diabetes in this setting by promoting Tregs that function in a TGF-␤-dependent manner. This finding contrasts with a large body of work suggesting that CD4 ؉ CD25 high Tregs act in a cytokine-independent manner, thus suggesting that another type of Treg is operational in this setting. We sought to determine the basis of suppression both in untreated NOD mice and in those treated with anti-CD3. Our present results show that a subset of foxP3 ؉ cells present within a CD4 ؉ CD25 low lymphocyte subset suppresses T cell immunity in spontaneously diabetic NOD mice in a TGF-␤-dependent manner, a functional property typical of ''adaptive'' regulatory T cells. This distinct Treg subset is evident in NOD, but not normal, mice, suggesting that the NOD mice may generate these adaptive Tregs in an attempt to regulate ongoing autoimmunity. Importantly, in two distinct in vivo models, these TGF-␤-dependent adaptive CD4 ؉ CD25 low T cells can be induced from peripheral CD4 ؉ CD25 ؊ T lymphocytes by anti-CD3 immunotherapy which correlates with the restoration of self-tolerance.autoimmunity ͉ immune tolerance ͉ foxP3 ͉ nonobese diabetic mice ͉ CD25 ϩ T cells

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“…Forkhead/winged-helix protein Foxp3 is critical for the development and function of regulatory T cells (12,13,37). It is considered as the most specific marker to date to identify CD4 + CD25 + T reg cells.…”

Section: Intracellular Foxp3 Levels Are Almost Similar In Wild Type Amentioning

confidence: 99%

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

et al. 2008

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A subset of CD4 + T cells, the CD4 + CD25 + T reg cells in the lymphoid organs and peripheral blood are known to possess suppressive function. Previous in vitro and in vivo studies have indicated that T cell receptor (TCR) signal is required for development of such 'natural regulatory (T reg ) cells' and for activation of the effector function of CD4 + CD25 + regulatory T cells. CD5 is a cell surface molecule present on all T cells and a subtype of B lymphocytes, the B-1 cells, primarily localized to coelomic cavities, Peyer's patches, tonsils and spleen. CD5 acts as a negative regulator of T cell and B cell signaling via recruitment of SHP-1. Here, we demonstrate that T reg cells obtained from CD5 −/− mice are more potent than those from wild type mice in suppressing the in vitro cell proliferation of anti-CD3 stimulated CD4 + CD25 − responder T cells. This phenomenon was cell contact and GITR dependent. Lack of CD5 expression on T reg cells (from spleen, lymph node and thymus) did not affect the intracellular levels of Foxp3. However, CD5 −/− T reg thymocytes were able to elicit a higher Ca 2+ response to TCR + co-stimulatory signals than the wild type cells. CD5 −/− mice expressed more Foxp3 mRNA in the colon than wild type mice, and additionally, the severity of the DSS-induced colitis in CD5 −/− mice was less than the wild type strain. We suggest that manipulation of CD5 expression or the downstream signaling components of CD4 + CD25 + T reg cells as a potential strategy for therapeutic intervention in cases of auto-immune disorders.

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The role of the transcription factor Foxp3 in the development of regulatory T cells

Cited by 161 publications

References 74 publications

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

Adaptive TGF-β-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

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The role of the transcription factor Foxp3 in the development of regulatory T cells

Cited by 161 publications

References 74 publications

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

Adaptive TGF-β-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

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Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling