IL-2, -7, and -15, but Not Thymic Stromal Lymphopoeitin, Redundantly Govern CD4+Foxp3+ Regulatory T Cell Development

Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2008; 181(5):3285-90. DOI: 10.4049/jimmunol.181.5.3285
Source: PubMed


Common gamma chain (gammac)-receptor dependent cytokines are required for regulatory T cell (Treg) development as gammac(-/-) mice lack Tregs. However, it is unclear which gammac-dependent cytokines are involved in this process. Furthermore, thymic stromal lymphopoietin (TSLP) has also been suggested to play a role in Treg development. In this study, we demonstrate that developing CD4(+)Foxp3(+) Tregs in the thymus express the IL-2Rbeta, IL-4Ralpha, IL-7Ralpha, IL-15Ralpha, and IL-21Ralpha chains, but not the IL9Ralpha or TSLPRalpha chains. Moreover, only IL-2, and to a much lesser degree IL-7 and IL-15, were capable of transducing signals in CD4(+)Foxp3(+) Tregs as determined by monitoring STAT5 phosphorylation. Likewise, IL-2, IL-7, and IL-15, but not TSLP, were capable of inducing the conversion of CD4(+)CD25(+)Foxp3(-) thymic Treg progenitors into CD4(+)Foxp3(+) mature Tregs in vitro. To examine this issue in more detail, we generated IL-2Rbeta(-/-) x IL-7Ralpha(-/-) and IL-2Rbeta(-/-) x IL-4Ralpha(-/-) mice. We found that IL-2Rbeta(-/-) x IL-7Ralpha(-/-) mice were devoid of Tregs thereby recapitulating the phenotype observed in gammac(-/-) mice; in contrast, the phenotype observed in IL-2Rbeta(-/-) x IL-4Ralpha(-/-) mice was comparable to that seen in IL-2Rbeta(-/-) mice. Finally, we observed that Tregs from both IL-2(-/-) and IL-2Rbeta(-/-) mice show elevated expression of IL-7Ralpha and IL-15Ralpha chains. Addition of IL-2 to Tregs from IL-2(-/-) mice led to rapid down-regulation of these receptors. Taken together, our results demonstrate that IL-2 plays the predominant role in Treg development, but that in its absence the IL-7Ralpha and IL-15Ralpha chains are up-regulated and allow for IL-7 and IL-15 to partially compensate for loss of IL-2.

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    • "FoxP3 binds to the promoter of bic, the gene encoding microRNA-155 [99-101]. T-cell receptor (TCR) and Notch signalling upregulate the IL-2R α-chain (CD25), rendering thymocytes receptive to subsequent cytokine signals that foster their development into fully functional FoxP3+ Tregs [102-104]. IL-2 is capable of transducing signals in CD4+FoxP3+ Tregs as determined by phosphorylation of signal transducer and activator of transcription 5 (STAT5) [104]. Deletion of microRNA-155 results in limited IL-2/STAT5 signalling, which reduced Treg numbers [105]. "
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    ABSTRACT: This article provides a new view of the cellular mechanisms that have been proposed to explain the links between infant formula feeding and the development of atopy and obesity. Epidemiological evidence points to an allergy- and obesity-preventive effect of breastfeeding. Both allergy and obesity development have been traced back to accelerated growth early in life. The nutrient-sensitive kinase mTORC1 is the master regulator of cell growth, which is predominantly activated by amino acids. In contrast to breastfeeding, artificial infant formula feeding bears the risk of uncontrolled excessive protein intake overactivating the infant's mTORC1 signalling pathways. Overactivated mTORC1 enhances S6K1-mediated adipocyte differentiation, but negatively regulates growth and differentiation of FoxP3(+) regulatory T-cells (Tregs), which are deficient in atopic individuals. Thus, the "early protein hypothesis" not only explains increased mTORC1-mediated infant growth but also the development of mTORC1-driven diseases such as allergy and obesity due to a postnatal deviation from the appropriate axis of mTORC1-driven metabolic and immunologic programming. Remarkably, intake of fresh unpasteurized cow's milk exhibits an allergy-preventive effect in farm children associated with increased FoxP3(+) Treg numbers. In contrast to unprocessed cow's milk, formula lacks bioactive immune-regulatory microRNAs, such as microRNA-155, which plays a major role in FoxP3 expression. Uncontrolled excessive protein supply by formula feeding associated with the absence of bioactive microRNAs and bifidobacteria in formula apparently in a synergistic way result in insufficient Treg maturation. Treg deficiency allows Th2-cell differentiation promoting the development of allergic diseases. Formula-induced mTORC1 overactivation is thus the critical mechanism that explains accelerated postnatal growth, allergy and obesity development on one aberrant pathway.
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    • "FoxP3, which is highly expressed in Tregs, binds to the promoter of bic, the gene encoding miR-155 [40,50,51]. TCR and Notch signaling upregulates the IL-2R α-chain (CD25), rendering thymocytes receptive to subsequent cytokine signals that foster their development into fully functional FoxP3+ Tregs [52-54]. IL-2 is capable of transducing signals in CD4+FoxP3+ Tregs as determined by STAT5 phosphorylation [54]. "
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    • "IL-2 shares the IL-2/15Rβ receptor with IL-15, and the γc receptor (CD132) with both IL-15 and IL-7. IL-2 is the dominant cytokine required for Treg survival and homeostasis, as the loss of IL-15 or IL-7 signaling does not substantially affect the frequency of CD4+ cells that are Treg when IL-2 is present (Burchill et al., 2007; Bayer et al., 2008; Vang et al., 2008). However, CD132 and to a lesser extent CD122-deficient mice have a more profound loss of Treg compared to IL-2 or CD25 deficient mice, suggesting that IL-15 and/or other γc cytokines also contribute to Treg homeostasis (Fontenot et al., 2005a). "
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