A Two-Step Process for Thymic Regulatory T Cell Development

Lio, Chan-Wang Jerry; Hsieh, Chyi-Song

doi:10.1016/j.immuni.2007.11.021

Cited by 558 publications

(666 citation statements)

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“…Finally, other signals involved in the generation and/or maintenance of nTreg development include costimulatory molecules such as CD28 and B7 [23,24] and cytokines such as IL-2, IL-7 [25], IL-15 [26] and thymic stromal lymphopoietin [27].…”

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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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: 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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“…It remains to be determined as to whether the T cells upon stimulation by the DC [51], or DC themselves, or both of the cell types together, could be the direct source of IL-2. In addition, DC can also produce IL-15 [48,49,54], but whether or not and how this cytokine is involved in Treg induction is still to be clarified [53,55]. We showed that, in contrast to the MRL/+ Treg, MRL/lpr Treg were unresponsive to exogenous IL-15 in the presence of either MRL/+ or MRL/lpr DC.…”

Section: Discussionmentioning

confidence: 80%

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

et al. 2008

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Regulatory T cell deficiency is evident in patients with lupus, but the casual relationship and underlying mechanism leading to Treg deficiency are unclear. We analyzed the Treg profile, induction and functions of Treg in a lupus mouse model. A characteristic agedependent biphasic change of Treg frequency was observed in the MRL/lpr mice, which developed a spontaneous lupus-like disease. After an early increase, Treg frequency in the peripheral lymphoid organs rapidly declined with age. Functionally, Treg from both young and old MRL/lpr mice were fully competent in suppressing the wild-type MRL/+ T effector cell (Teff) responses. Adoptive transfer of MRL/+ Treg markedly suppressed clinical disease in the MRL/lpr mice. We demonstrated that the reduced Treg frequency was a result of insufficient peripheral Treg expansion due to defective MRL/lpr Teff in IL-2 production, and the associated defects in dendritic cells, which could be fully restored by exogenous IL-2. In the absence of IL-2, MRL/lpr Teff but not MRL/lpr Treg were highly responsive to IL-15 and could expand rapidly due to enhanced IL-15R expression and IL-15 synthesis. These findings thus provide a clear causal relationship and immunological mechanism underlying Treg deficiency and systemic autoimmunity.

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“…Then, IL-2 signaling induces Foxp3 expression that, in turn, strengthens Treg-cell lineage stability [1,2]. These three successive events are now well recognized to be important steps of thymic Treg-cell development.…”

Section: Discussionmentioning

confidence: 99%

“…Natural Treg cells arise in the thymus where T-cell receptor (TCR) signals lead to interleukin (IL)-2 sensitivity enhancement in developing thymocytes. Then, IL-2 signaling induces Foxp3 expression that, in turn, strengthens Treg-cell lineage stability [1,2]. Foxp3 expression is Correspondence: Dr. Bruno Lucas e-mail: bruno.lucas@inserm.fr then important to maintain a distinct transcriptional program required for their suppressive function [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…Natural Treg cells arise in the thymus where T-cell receptor (TCR) signals lead to interleukin (IL)-2 sensitivity enhancement in developing thymocytes. Then, IL-2 signaling induces Foxp3 expression that, in turn, strengthens Treg-cell lineage stability [1,2]. Foxp3 expression is overlap (10-20%) between the TCR sequences expressed within the conventional CD4 + T (Tconv) cell and the Treg-cell repertoire [10].…”

Section: Introductionmentioning

confidence: 99%

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Foxp3‐independent loss of regulatory CD4⁺T‐cell suppressive capacities induced by self‐deprivation

et al. 2012

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In the periphery, Foxp3 expression is considered sufficient to maintain natural regulatory CD4 + T-cell suppressive function. In this study, we challenge this model. Indeed, in mouse chimeras in which major histocompatibility complex (MHC) class II expression is restricted to the thymus, peripheral regulatory CD4 + T cells lack suppressive activity. In addition, regulatory CD4 + T cells recovered 5 days after transfer into recipient mice lacking expression of MHC class II molecules (self-deprived) are unable to inhibit the proliferative response of conventional CD4 + T cells both in vitro and in vivo. Disruption of TCR/MHC class II interactions rapidly leads to alterations in the regulatory CD4 + T-cell phenotype, the ability to respond to stimulation and to produce interleukin-10, and the transcriptional signature. Interestingly, self-deprivation does not affect Foxp3 expression indicating that in regulatory CD4 + T cells, self-recognition induces unique transcriptional and functional features that do not rely on Foxp3 expression. Keywords: Autoreactivity r Foxp3 r Regulatory T cells Supporting Information available online IntroductionNaturally occurring regulatory CD4 + T (Treg) cells are important for the maintenance of self-tolerance in the periphery. In particular, they are key players in the prevention of various autoimmune and inflammatory disorders. Natural Treg cells arise in the thymus where T-cell receptor (TCR) signals lead to interleukin (IL)-2 sensitivity enhancement in developing thymocytes. Then, IL-2 signaling induces Foxp3 expression that, in turn, strengthens Treg-cell lineage stability [1,2]. Foxp3 expression is Correspondence: Dr. Bruno Lucas e-mail: bruno.lucas@inserm.fr then important to maintain a distinct transcriptional program required for their suppressive function [3][4][5].Recent studies have clearly established that the TCR has an instructive role in inducing commitment of developing thymocytes into the Treg-cell lineage [6,7]. More precisely, Treg-cell development would be instructed by TCRs with high avidity for self-peptides bound to major histocompatibility complex (MHC) class II molecules (self). Indeed, the proportion of Treg cells is increased when TCR transgenic T cells are forced to see their cognate antigens in the thymus [1,2,8,9]. This model is further supported by the observation that there is a limited amount of * These authors contributed equally to this work. overlap (10-20%) between the TCR sequences expressed within the conventional CD4 + T (Tconv) cell and the Treg-cell repertoire [10]. Interestingly, overlapping is more important when the Tregcell repertoire was compared with the repertoire of pathogenic autoreactive effector T cells [11]. After migrating to the periphery, Treg cells still interact with self. Indeed, based on autoimmune ovarian disease and prostatitis models, Tung and colleagues [12,13] have determined that continuous interactions with self are required to allow Treg cells to accumulate in the draining lymph-nodes. More recently, Lathrop et al. ...

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A Two-Step Process for Thymic Regulatory T Cell Development

Cited by 558 publications

References 45 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

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

Foxp3‐independent loss of regulatory CD4⁺T‐cell suppressive capacities induced by self‐deprivation

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A Two-Step Process for Thymic Regulatory T Cell Development

Cited by 558 publications

References 45 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

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

Foxp3‐independent loss of regulatory CD4+T‐cell suppressive capacities induced by self‐deprivation

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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

Foxp3‐independent loss of regulatory CD4⁺T‐cell suppressive capacities induced by self‐deprivation