A function for IL-7r for CD4+ CD25+ Foxp3+ T regulatory cells

Department of Microbiology and Immunology, Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
The Journal of Immunology (Impact Factor: 4.92). 08/2008; 181(1):225-34.
Source: PubMed


The IL-2/IL-2R interaction is important for development and peripheral homeostasis of T regulatory (Treg) cells. IL-2- and IL-2R-deficient mice are not completely devoid of Foxp3+ cells, but rather lack population of mature CD4+CD25+Foxp3high Treg cells and contain few immature CD4+CD25-Foxp3low T cells. Interestingly, common gamma chain (gammac) knockout mice have been shown to have a near complete absence of Foxp3+ Treg cells, including the immature CD25-Foxp3low subset. Therefore, other gammac-cytokine(s) must be critically important during thymic development of CD4+CD25+Foxp3+ Treg cells apart from the IL-2. The present study was undertaken to determine whether the gammac-cytokines IL-7 or IL-15 normally contribute to expression of Foxp3 and Treg cell production. These studies revealed that mice double deficient in IL-2Rbeta and IL-7Ralpha contained a striking lack in the CD4+Foxp3+ population and the Treg cell defect recapitulated the gammac knockout mice. In the absence of IL-7R signaling, IL-15/IL-15R interaction is dispensable for the production of CD4+CD25+Foxp3+ Treg cells, indicating that normal thymic Treg cell production likely depends on signaling through both IL-2 and IL-7 receptors. Selective thymic reconstitution of IL-2Rbeta in mice double deficient in IL-2Rbeta and IL-7Ralpha established that IL-2Rbeta is dominant and sufficient to restore production of Treg cells. Furthermore, the survival of peripheral CD4+Foxp3low cells in IL-2Rbeta-/- mice appears to depend upon IL-7R signaling. Collectively, these data indicate that IL-7R signaling contributes to Treg cell development and peripheral homeostasis.

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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 T reg survival and homeostasis, as the loss of IL-15 or IL-7 signaling does not substantially affect the frequency of CD4 + cells that are T reg 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 T reg compared to IL-2 or CD25 deficient mice, suggesting that IL-15 and/or other γc cytokines also contribute to T reg homeostasis (Fontenot et al., 2005a). "
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    ABSTRACT: We and others have shown that regulatory T cells (Treg) accumulate dramatically with age in both humans and mice. Such Treg accrual contributes to age-related immunosenescence as they reduce the response to tumors and parasite infection. While we reported earlier that aged Treg have decreased expression of the pro-apoptotic molecule Bim and germline deletion of Bim promoted earlier accumulation of Treg, it remains unclear whether the effects of Bim are: (i) Treg intrinsic and (ii) dominant to other BH3-only pro-apoptotic molecules. Further, the mechanism(s) controlling Bim expression in aged Treg remain unclear. Here we show that Treg-specific loss of Bim is sufficient to drive Treg accrual with age and that additional loss of the downstream apoptotic effectors Bax and Bak did not exacerbate Treg accumulation. Further, our results demonstrate that a subpopulation of Treg expands with age and is characterized by lower expression of CD25 (IL-2Rα) and Bim. Mechanistically, we found that IL-2 levels decline with age and likely explain the emergence of CD25(lo)Bim(lo) Treg because Treg in IL-2(-/-) mice are almost entirely comprised of CD25(lo)Bim(lo) cells, and IL-2 neutralization increases CD25(lo)Bim(lo) Treg in both young and middle-aged mice. Interestingly, the Treg population in aged mice had increased expression of CD122 (IL-2/IL-15Rβ) and neutralization or genetic loss of IL-15 led to less Treg accrual with age. Further, the decreased Treg accrual in middle-aged IL-15(-/-) mice was restored by the additional loss of Bim (IL-15(-/-)Bim(-/-)). Together, our data show that aging favors the accrual of CD25(lo) Treg whose homeostasis is supported by IL-15 as IL-2 levels become limiting. These data have implications for manipulating Treg to improve immune responses in the elderly.
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    • "The only important exception seems to be represented by CD4+ FOXP3+ Treg which have been reported to express low levels of the IL-7 receptor alpha chain (CD127) [21]–[23]. Accordingly, peripheral Treg biology is believed to be essentially independent of IL-7/IL-7Rα signaling [17], [24]–[28] although Bayer et al suggested that IL-7 could contribute to Treg homeostasis when IL-2 signaling is disrupted [24]. However, we and others have previously shown that in vitro IL-7 treatment induces significant STAT5 phosphorylation in Tregs [26], [29]–[31] and that IL-7 is able to increase in vitro Treg survival [30], [32], [33]. "
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