Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo

Gavin, Marc A.; Clarke, Sally R. M.; Negrou, Ella; Gallegos, Alena M.; Rudensky, Alexander Y.

doi:10.1038/ni743

Cited by 602 publications

(534 citation statements)

References 71 publications

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“…This provides direct evidence for PD-1 as a negative regulator of immune responses in vivo [13]. PD-1 mRNA is expressed at high levels in CD4 + CD25 + regulatory T cells (Treg) and anergic T cells [14,15], suggesting the possible involvement of PD-1 in regulating Treg function and T cell tolerance.…”

Section: Introductionmentioning

confidence: 73%

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

et al. 2004

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Programmed death-1 ligand 2 (PD-L2) is a ligand for programmed death-1 (PD-1), a receptor that plays an inhibitory role in T cell activation. Since previous studies have shown upregulation of PD-L2 expression by Th2 cytokines, and asthma is driven by a Th2 response, we hypothesized that PD-L2 might be involved in regulation of the immune response in this disease. We have found that lungs from asthmatic mice had sustained up-regulation of PD-1 and PD-L2, with PD-L2 primarily on dendritic cells. Although addition of PD-L2-Fc in vitro led to decreased T cell proliferation and cytokine production, administration of PD-L2-Fc in vivo in a mouse asthma model resulted in elevated serum IgE levels, increased eosinophilic and lymphocytic infiltration into bronchoalveolar lavage fluid, higher number of cells in the draining lymph nodes, and production of IL-5 and IL-13 from these cells. Although PD-1 was expressed on regulatory T cells, PD-L2-Fc did not affect regulatory T cell activity in vitro. This study provides in vivo evidence of an exacerbated inflammatory response following PD-L2-Fc administration and indicates a potential role for this molecule in Th2-mediated diseases such as asthma.

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Section: Introductionmentioning

confidence: 73%

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

et al. 2004

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“…T reg homeostasis requires continuous interaction with DC presenting self-peptide [19,21]. Recently, it has been shown that T reg proliferate in vivo vigorously in response to antigen stimulation [22], and that mature DC are responsible for such Ag-induced T reg proliferation [10], reverting the general belief that T reg constitute an anergic population.…”

Section: Discussionmentioning

confidence: 99%

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

et al. 2005

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CD4 + CD25 + regulatory T cells (T reg) development and homeostasis require IL-2 and costimulation through same TNF-receptor family members. CD40KO mice have reduced number of T reg in peripheral blood, thymus and spleen. Herein we show that naive T reg express low basal level of CD40L that is upregulated upon TCR-triggered mediated activation. Treatment of wt mice with Ab blocking CD40/CD40L interaction results in a fast decrease in T reg number that rapidly recovers upon Ab withdrawal. CFSE-labeled T reg from wt mice injected into CD40KO, but not wild-type (wt) mice, showed reduced survival and proliferation in homeostatic setting. In vitro, dendritic cells from CD40KO mice but not wt mice produce diminished amount of IL-2 upon T reg encounter and are impaired in expanding T reg, a defect corrected by the addition of rIL-2. Accordingly, four daily IL-2 administrations to CD40KO mice normalize T reg number by promoting both their survival and homeostatic proliferation. Such IL-2 effect is transient since T reg number returns to the low constitutive level described in CD40KO mice within 5 days upon IL-2 withdrawal thus suggesting that IL-2 is persistently needed to assure T reg homeostasis.

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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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Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo

Cited by 602 publications

References 71 publications

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

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

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Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo

Cited by 602 publications

References 71 publications

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

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

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CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2