Trends in Immunology
Volume 32, Issue 1, January 2011, Pages 26-33
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Review
Foxo: in command of T lymphocyte homeostasis and tolerance

https://doi.org/10.1016/j.it.2010.10.005Get rights and content

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.

Section snippets

Foxo protein and its ancient biological function

The forkhead box (Fox) family of transcription factors is named after the Drosophila melanogaster gene fkh (fork head); mutation of which causes developmental defects with a spiked head appearance in adult flies [1]. Characterized by the presence of a winged helix forkhead DNA-binding domain, over 40 structurally related Fox proteins have been identified in mammals, which are further classified into subfamilies on the basis of their sequence homology [2]. There are four “O” subfamily members of

Control of T cell trafficking by Foxo proteins

A functional adaptive immune system depends on a diverse and self-tolerant population of T cells that are generated in the thymus, and are maintained in the peripheral lymphoid organs. Thymocytes undergo selection processes to become mature CD4+ or CD8+ T cells that are endowed with the capability to emigrate from the thymus. Thymic exit of T cells and their migration into peripheral lymphoid organs depend on the expression of a set of trafficking molecules including sphingosine-1-phosphate

Foxo proteins, T cell survival and homeostatic proliferation

Naïve T cells are well maintained in the peripheral lymphoid organs by homeostatic processes that are dependent on the common γ-chain cytokine IL-7 [26]. IL-7 regulates T cell survival and homeostatic proliferation, in part, through activation of the Janus kinase/signal transducers and activators of transcription pathway, and induction of the anti-apoptotic protein Bcl-2 [27]. IL-7 is constitutively produced by lymphoid stromal cells, therefore, T cell responsiveness to IL-7 is primarily

Foxo proteins regulate T cell tolerance

The stochastic process by which the TCR is generated creates an inherent problem of some T cells bearing high-affinity TCRs to self-antigens. Despite thymic negative selection, a proportion of self-reactive T cells are released to peripheral tissues. The “escaped” autoreactive T cells are restrained from provoking autoimmune disease by multiple mechanisms. Studies over the past 15 years have established CD4+CD25+ regulatory T (Treg) cells as pivotal regulators of peripheral T cell tolerance [33]

Foxo protein regulation of nTreg cell differentiation

An outstanding question in the Treg cell field is how Treg cell lineage is specified during T cell development 41, 42. Treg cells exhibit an “antigen-experienced” phenotype, which suggests that their differentiation is induced or accompanied by exposure to high-affinity self-antigens. Recent studies of transgenic mice that express TCRs derived from Treg cells have demonstrated that nTreg cell differentiation is instructed by TCR specificity 43, 44, 45. In one strain of such TCR-transgenic mice,

Foxo proteins and iTreg cell differentiation

Besides thymic production of nTreg cells, peripheral naïve CD4+ T cells can acquire Foxp3 expression, and differentiate into iTreg cells. However, compared to mature thymic CD4+ T cells, peripheral T cells are much less efficient in turning on Foxp3 expression when subject to the same activation–resting protocol 25, 66. These findings imply that additional signals are required to trigger Foxp3 expression in peripheral T cells. Indeed, the cytokine transforming growth factor (TGF)-β has been

Concluding remarks

Foxo proteins are important regulators of energy metabolism and stress responses that are highly conserved during evolution. Studies in the past few years have started to reveal pleiotropic yet crucial roles for Foxo proteins in the mammalian adaptive immune system. The first discoveries about Foxo proteins in T cells demonstrated their pivotal functions in the control of T cell migration, survival and tolerance, which are functions that are partly mediated by Foxo protein regulation of immune

Acknowledgements

Work in our laboratory is supported by grants from the National Institute of Arthritis, Musculoskeletal and Skin Diseases (KO1 AR053595 and RO1 AR060723), the Starr Cancer Consortium (13-A123), the Arthritis Foundation and the Rita Allen Foundation.

References (74)

  • Z. Tothova

    FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress

    Cell

    (2007)
  • J.H. Paik

    FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis

    Cell

    (2007)
  • S.Z. Josefowicz et al.

    Control of regulatory T cell lineage commitment and maintenance

    Immunity

    (2009)
  • J. Schulze-Luehrmann et al.

    Antigen-receptor signaling to nuclear factor kappa B

    Immunity

    (2006)
  • M. Schmidt-Supprian

    Mature T cells depend on signaling through the IKK complex

    Immunity

    (2003)
  • S. Gupta

    Differential requirement of PKC-theta in the development and function of natural regulatory T cells

    Mol. Immunol.

    (2008)
  • M. Long

    Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor

    Immunity

    (2009)
  • Q. Ruan

    Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome

    Immunity

    (2009)
  • J.D. Fontenot

    Regulatory T cell lineage specification by the forkhead transcription factor foxp3

    Immunity

    (2005)
  • C.W. Lio et al.

    A two-step process for thymic regulatory T cell development

    Immunity

    (2008)
  • M.O. Li et al.

    TGF-beta: a master of all T cell trades

    Cell

    (2008)
  • W. Ouyang

    Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development

    Immunity

    (2010)
  • D.A. Guertin

    Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1

    Dev. Cell

    (2006)
  • G.M. Delgoffe

    The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment

    Immunity

    (2009)
  • K. Lee

    Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways

    Immunity

    (2010)
  • K.H. Kaestner

    Unified nomenclature for the winged helix/forkhead transcription factors

    Genes Dev.

    (2000)
  • D.R. Calnan et al.

    The FoxO code

    Oncogene

    (2008)
  • K.E. van der Vos et al.

    FOXO-binding partners: it takes two to tango

    Oncogene

    (2008)
  • K.C. Arden

    FOXO animal models reveal a variety of diverse roles for FOXO transcription factors

    Oncogene

    (2008)
  • A. Soulard et al.

    SnapShot: mTOR signaling

    Cell

    (2007)
  • J.H. Lee

    Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies

    Science

    (2010)
  • T. Becker

    FOXO-dependent regulation of innate immune homeostasis

    Nature

    (2010)
  • M.A. Weinreich et al.

    Thymic emigration: when and how T cells leave home

    J. Immunol.

    (2008)
  • M. Matloubian

    Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1

    Nature

    (2004)
  • T. Worbs

    CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo

    J. Exp. Med.

    (2007)
  • C.M. Carlson

    Kruppel-like factor 2 regulates thymocyte and T-cell migration

    Nature

    (2006)
  • E. Sebzda

    Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns

    Nat. Immunol.

    (2008)
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