Distinct IL-2 Receptor Signaling Pattern in CD4+CD25+ Regulatory T Cells

Bensinger, Steven J.; Walsh, Patrick; Zhang, Jidong; Carroll, Martin; Parsons, Ramon; Rathmell, Jeffrey C.; Thompson, Craig B.; Burchill, Matthew A.; Farrar, Michael A.; Turka, Laurence A.

doi:10.4049/jimmunol.172.9.5287

Cited by 253 publications

(243 citation statements)

References 46 publications

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“…As previously reported, T reg died more quickly than T eff [12]. Furthermore, IL-2 rescued significantly more T reg than T eff from cell death, which reflects the well known dependency of highly purified CD4 + CD25 high cells on exogenous IL-2 in vitro [35,36]. Most importantly, we did not detect an increase of apoptotic or necrotic cell death in T reg from MS patients (spontaneous apoptosis 45.2 AE 7.5% (MS, n=8) vs. 45.7 AE 5.0% (controls, n=8) (Fig.…”

Section: T Reg From Ms Patients Do Not Display Enhanced Sensitivity Tsupporting

confidence: 80%

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

et al. 2005

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Immunoregulatory T cells of CD4 + CD25 + phenotype suppress T cell function and protect rodents from organ-specific autoimmune disease. The human counterpart of this subset of T cells expresses high levels of CD25 and its role in human autoimmune disorders is currently under intense investigation. In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), the activation of circulating self-reactive T cells with specificity for myelin components is considered to be an important disease initiating event. Here, we investigated whether MS is associated with an altered ability of CD4 + CD25 high regulatory T cells (T reg ) to confer suppression of myelin-specific immune responses. Whereas T reg frequencies were equally distributed in blood and cerebrospinal fluid of MS patients and did not differ compared to healthy controls, the suppressive potency of patient-derived CD4 + CD25 high T lymphocytes was impaired. Their inhibitory effect on antigen-specific T cell proliferation induced by human recombinant myelin oligodendrocyte protein as well as on immune responses elicited by polyclonal and allogeneic stimuli was significantly reduced compared to healthy individuals. The effect was persistent and not due to responder cell resistance or altered survival of T reg , suggesting that a defective immunoregulation of peripheral T cells mediated by CD4 + CD25 high T lymphocytes promotes CNS autoimmunity in MS.

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Section: T Reg From Ms Patients Do Not Display Enhanced Sensitivity Tsupporting

confidence: 80%

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

et al. 2005

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“…Interestingly, Bensinger et al [67] recently showed that peripheral Treg, stimulated in the presence of IL-2, show increased survival in the absence of Akt phosphorylation, suggesting that Akt activation is dispensable for Treg survival.…”

Section: Discussionmentioning

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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“…While knockout animal models have yielded contradictory results, in vitro signaling studies have indicated that IL-2R has different signaling properties in Treg when compared to conventional CD4 + T cells [33]. Specifically, IL-2R signaling activates STAT5, but not protein kinase B/Akt, due to the constitutive expression of phosphatidylinositol-phosphatase, phosphatase and tensin homolog deleted on chromosome 10 (PTEN).…”

Section: Discussionmentioning

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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Distinct IL-2 Receptor Signaling Pattern in CD4+CD25+ Regulatory T Cells

Cited by 253 publications

References 46 publications

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

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

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

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Distinct IL-2 Receptor Signaling Pattern in CD4+CD25+ Regulatory T Cells

Cited by 253 publications

References 46 publications

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

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

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

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