Foxo: in command of T lymphocyte homeostasis tolerance

Immunology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Trends in Immunology (Impact Factor: 10.4). 01/2011; 32(1):26-33. DOI: 10.1016/
Source: PubMed

ABSTRACT The forkhead box O (Foxo) family of transcription factors consists of the mammalian orthologs of the Caenorhabditis elegans longevity protein Daf-16, and has an evolutionarily conserved function in the regulation of nutrient sensing and stress responses. Recent studies have shown that Foxo proteins control expression of immune system-specific genes such as Il7ra in naïve T cells and Foxp3 in regulatory T cells, which are crucial regulators of T cell homeostasis and tolerance. These findings reveal that the ancient Foxo pathway has been co-opted to regulate highly specialized T cell activities. The Foxo pathway probably enables a diverse and self-tolerant population of T cells in the steady state, which is an important prerequisite for the establishment of a functional adaptive immune system.

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    • "FOXO transcription factors are important for the expression of cyclindependent kinase inhibitors and proapoptotic molecules, and thus their inhibition is an essential aspect of growth factormediated cell-cycle progression and survival. In T cells, FOXO transcription factors have been shown to regulate multiple, specialized functions including the expression of the Il7ra and Klf2—control points for T cell survival and homing (Ouyang and Li, 2011; Hedrick et al., 2012). In addition, mice with a T cell-specific deletion of Foxo1 lack functional FOXP3 + Treg cells and spontaneously develop systemic autoimmunity. "
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    ABSTRACT: T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1(-/-) GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 02/2015; 42(2):239-51. DOI:10.1016/j.immuni.2015.01.017 · 21.56 Impact Factor
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    • "That maintenance of mTreg cells in the skin is IL-7-dependent raises the important question of how expression of IL-7R is regulated in these cells in such a tissue-specific manner. Expression of IL-7R in conventional T cells is controlled in large part by the transcription factor, Foxo1, which in T cells is inactivated and removed from the nucleus after phosphorylation by activated Akt following TCR stimulation (173). However, despite the fact that Treg cells rely on continued Foxo1 activity for their suppressive function, most Treg cells in secondary lymphoid organs express low levels of IL-7R (49, 174). "
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    ABSTRACT: Foxp3(+) regulatory T cells (Treg cells) are essential for establishing and maintaining self-tolerance, and also inhibit immune responses to innocuous environmental antigens. Imbalances and dysfunction in Treg cells lead to a variety of immune-mediated diseases, as deficits in Treg cell function contribute to the development autoimmune disease and pathological tissue damage, whereas overabundance of Treg cells can promote chronic infection and tumorigenesis. Recent studies have highlighted the fact that Treg cells themselves are a diverse collection of phenotypically and functionally specialized populations, with distinct developmental origins, antigen-specificities, tissue-tropisms, and homeostatic requirements. The signals directing the differentiation of these populations, their specificities and the mechanisms by which they combine to promote organ-specific and systemic tolerance, and how they embody the emerging property of regulatory memory are the focus of this review.
    Frontiers in Immunology 07/2014; 5:333. DOI:10.3389/fimmu.2014.00333
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    • "Unlike the seemingly opposing effects on T cell survival, FOXO1 and FOXO3 co-operatively protect against autoimmunity. Loss of FOXO1 and FOXO3 in T cells results in uncontrolled T cell activation and autoimmunity, which is at least in part linked to defects in the generation of regulatory T cells (Ouyang and Li, 2011). In addition, disruption of T cell homeostasis in the absence of FOXOs could result from dysregulated expression of p15Ink4b, p21Cip1, and p27Kip1 by itself and/or in association with TGF-β/Smad signaling pathway (Ouyang et al., 2010; Hedrick et al., 2012). "
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    ABSTRACT: The clonal expansion, differentiation into effectors and establishing an immunological memory are crucial components of the adaptive immune response. Following the initial encounter with a pathogen, clonal CD8 T cell expansion yields at least two distinct populations of effector cells, short-lived effector cells (SLECs) and memory precursor effector cells (MPECs). SLECs are the terminally differentiated cells, which play an active role in pathogen clearance and undergo apoptosis once the pathogen is eliminated. In contrast, MPECs persist and give rise to self-renewing memory cells. These memory CD8 T cells maintain a state of heightened alertness and are poised to rapidly respond and swiftly clear the pathogen upon antigen re-encounter. As one of the goals of vaccination is to induce the development of these memory CD8 T cells, understanding the cellular and molecular basis of memory cell differentiation is critical to rational vaccine design. It is clear that memory differentiation is complex and involves multiple interrelated signaling pathways. It is influenced by factors such as the strength and duration of antigen receptor signaling and concurrent exposure to cytokines. Several signaling pathways that influence T cell fate have been recently described, and many culminate in the differential expression of specific transcription factors. Unfortunately, the mechanisms underlying the coordination and confluence these signaling pathways remain largely unknown. In this review, we will discuss the role of the PI3K signaling pathway as a central signaling node, and the function of Akt as a rheostat in orchestrating the differentiation of memory CD8 T cells.
    Frontiers in Immunology 02/2013; 4. DOI:10.3389/fimmu.2013.00020
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