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: 5.36). 08/2008; 181(1):225-34.
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    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.
    Frontiers in Immunology 06/2013; 4:161. DOI:10.3389/fimmu.2013.00161
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: According to the "two-step model," the intrathymic generation of CD4⁺ regulatory T (T(reg)) cells segregates into a first, T cell receptor (TCR)-driven phase and a second, cytokine-dependent phase. The initial TCR stimulus gives rise to a CD25⁺Foxp3⁻ developmental intermediate. These precursors subsequently require cytokine signaling to establish the mature CD25⁺Foxp3⁺ T(reg) cell phenotype. In addition, costimulation via CD28/B7 (CD80/86) axis is important for the generation of a T(reg) cell repertoire of normal size. Recent data suggest that CD28 or B7 deficient mice lack CD25⁺Foxp3⁻ T(reg) cell progenitors. However, these data leave open whether costimulation is also required at subsequent stages of T(reg) differentiation. Also, the fate of "presumptive" T(reg) cells carrying a permissive TCR specificity in the absence of costimulation remains to be established. Here, we have used a previously described TCR transgenic model of agonist-driven T(reg) differentiation in order to address these issues. Intrathymic adoptive transfer of T(reg) precursors indicated that costimulation is dispensable once the intermediate CD25⁺Foxp3⁻ stage has been reached. Furthermore, lack of costimulation led to the physical loss of presumptive T(reg) cells rather than their escape from central tolerance and differentiation into the conventional CD4⁺ T cell lineage. Our findings suggest that CD28 signaling does not primarily operate through enhancing the TCR signal strength in order to pass the threshold intensity required to initiate T(reg) cell specification. Instead, costimulation seems to deliver unique and qualitatively distinct signals that coordinately foster the developmental progression of T(reg) precursors and prevent their negative selection.
    Frontiers in Immunology 07/2011; 2:30. DOI:10.3389/fimmu.2011.00030
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Members of the Forkhead box O (Foxo) family of transcription factors are key regulators of cellular responses, but their function in the immune system remains incompletely understood. Here we showed that T cell-specific deletion of Foxo1 gene in mice led to spontaneous T cell activation, effector T cell differentiation, autoantibody production, and the induction of inflammatory bowel disease in a transfer model. In addition, Foxo1 was critical for the maintenance of naive T cells in the peripheral lymphoid organs. Transcriptome analyses of T cells identified Foxo1-regulated genes encoding, among others, cell-surface molecules, signaling proteins, and nuclear factors that control gene expression. Functional studies validated interleukin-7 receptor-alpha as a Foxo1 target gene essential for Foxo1 maintenance of naive T cells. These findings reveal crucial functions of Foxo1-dependent transcription in control of T cell homeostasis and tolerance.
    Immunity 04/2009; 30(3):358-71. DOI:10.1016/j.immuni.2009.02.003 · 19.75 Impact Factor


1 Download
Available from

Similar Publications