CD25+ CD4+ T Cells Regulate the Expansion of Peripheral CD4 T Cells Through the Production of IL-10

Annacker, Oliver; Pimenta-Araujo, Ricardo; Burlen-Defranoux, Odile; Barbosa, Theolis; Cumano, Ana; Bandeira, António

doi:10.4049/jimmunol.166.5.3008

Cited by 496 publications

(439 citation statements)

References 43 publications

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“…Two weeks later, absolute numbers of CD4 + T cells recovered from the periphery of injected mice were estimated. As previously described [20], with such a ratio, control Treg cells significantly inhibited the initial expansion of CD4 + Tconv cells (Fig. 4B).…”

Section: Self-deprived Treg Cells Are Not Functionalsupporting

confidence: 85%

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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Section: Self-deprived Treg Cells Are Not Functionalsupporting

confidence: 85%

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

et al. 2012

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“…However, the dependence on IL-2 for Treg maintenance is only seen in lympho-replete animals. IL-2 is dispensable for the expansion of Treg in a lymphopenic host, suggesting that there are at least two mechanisms involved in Treg expansion and survival [22,23].…”

Section: Introductionmentioning

confidence: 99%

IL‐2Rβ links IL‐2R signaling with Foxp3 expression

2007

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Immunological tolerance to self antigens is a tightly regulated process. Recent work has demonstrated that the forkhead family member Foxp3 is a critical element in the differentiation and function of mouse CD4 + CD25 + regulatory T cells (Treg). Recent work has suggested an important role for IL-2 in the development and maintenance of Treg. To directly assess the effect of IL-2 signaling on Treg development and function, we analyzed mice that were genetically deficient in components of the IL-2 receptor (IL-2R). Mice lacking CD25 (IL-2Ra) displayed a slight decrease in Treg within the thymus, while peripheral numbers are unchanged. In contrast, we found that mice deficient in CD122 (IL-2Rb) had a profound reduction in both thymic and peripheral Treg, coinciding with more rapid development of a fatal lymphoproliferative disease. Expression of a Foxp3 transgene restored Treg and protected against the onset of autoimmunity. Thus, a signal mediated by IL-2Rb is essential for the development and homeostasis of Foxp3 + Treg in vivo.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/37101_s.pdf IntroductionPeripheral tolerance to self antigens is regulated, in part, by a population of CD4 + CD25 + Foxp3 + regulatory T cells (Treg). Genetic lesions in the Foxp3 gene (the scurfy mutant mouse or human patients with immune dysfunction/polyendocrinopathy/enteropathy/X-linked syndrome) lack Treg and develop a fatal autoimmune lymphoproliferative disease [1][2][3][4][5][6][7]. A similar, but less severe, phenotype is observed in mice deficient in IL-2 and components of its receptor complex, . Thus, disrupting the IL-2R signaling pathway results in severe T cell-mediated autoimmunity rather than immune deficiency, indicating a significant role for IL-2R signaling in Treg development and function.Signaling through the IL-2R complex is initiated by ligand-induced heterodimerization of CD122 and CD132, which activates the associated tyrosine kinases JAK1 and JAK3. Since it has previously been shown that a covalently linked JAK3 molecule can functionally replace the cytoplasmic domain of CD132, the role of CD132 in IL-2R signaling appears to be restricted to the recruitment of JAK3 [13]. By contrast, CD122 provides essential docking sites for at least two major downstream signaling mediators, the adaptor protein Shc and the transcription factor STAT5. CD122 is common to both the IL-2R and IL-15R, with each receptor having a unique a chain that defines receptor specificity (IL-2Ra and IL-15Ra, respectively). Unlike CD122, the role of CD25 appears to be confined to increasing binding affinity (KD *10 -9 -10 -11 M) and it is postulated that the short cytoplasmic domain is unlikely to contribute to signaling [13][14][15][16][17][18].Several lines of evidence suggest that IL-2 is essential for the homeostatic proliferation of Treg. For example, bone marrow chimera studies showed that IL-2 production by non-Treg is required for Treg maintenance [19]. In addition, treatment of mice with...

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“…Interaction of T cells with MHC class I and class II-peptide complexes are required for homeostatic expansion of CD8 and CD4 T cell subpopulations, respectively [8,10,11,[13][14][15]. Two hypotheses have been proposed to explain homeostasis-driven T cell proliferation: the "space" hypothesis, which states that lymphopenia would create space for naive cells to expand and fill the empty niches [16][17][18]; and the suppressor cell hypothesis, which emphasizes that selective elimination of CD4 + CD25 + regulatory T cells by the lymphopenic insult would result in expansion of self-reactive T cells [19][20][21].…”

Section: Discussionmentioning

confidence: 99%

Anti‐tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution

Urba

Liu

et al. 2003

Eur J Immunol

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To test whether homeostasis-driven T cell proliferation in reconstituted lymphodepleted hosts would improve the therapeutic efficacy of tumor vaccines, normal mice and reconstituted lymphopenic mice (RLM; C57BL/6 mice rendered lymphopenic with sublethal totalbody irradiation and reconstituted with naive splenocytes) were used in the vaccination and challenge experiments with weakly immunogenic F10 melanoma cells. Only limited protection was observed in vaccinated normal mice (16.7%), whereas significantly greater protection was induced in vaccinated RLM (63.2%). Protective immunity in RLM depended on CD8 T cells. Following vaccination, a significant increase in the percentage of CD44 hi CD62L lo T cells was detected in the tumor vaccine-draining lymph node (TVDLN) of vaccinated RLM compared to that of vaccinated normal mice. After in vitro stimulation, effector T cells generated from TVDLN of vaccinated RLM produced more IFN-+ than T cells from vaccinated normal mice, and contained more melanoma-specific T cells, as assessed by ELISA and intracellular cytokine staining. This study suggests that vaccination of reconstituted lymphopenic hosts could elicit superior anti-tumor immunity compared to normal hosts, highlighting the potential clinical benefit of performing tumor vaccination during immune reconstitution.

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CD25+ CD4+ T Cells Regulate the Expansion of Peripheral CD4 T Cells Through the Production of IL-10

Cited by 496 publications

References 43 publications

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

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

IL‐2Rβ links IL‐2R signaling with Foxp3 expression

Anti‐tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution

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CD25+ CD4+ T Cells Regulate the Expansion of Peripheral CD4 T Cells Through the Production of IL-10

Cited by 496 publications

References 43 publications

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

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

IL‐2Rβ links IL‐2R signaling with Foxp3 expression

Anti‐tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution

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

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