Trends in Immunology
ReviewFoxo: in command of T lymphocyte homeostasis and tolerance
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)
The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo
Cell
(1989)FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor
Dev. Cell
(2010)- et al.
A key role for CCR7 in establishing central and peripheral tolerance
Trends Immunol.
(2007) KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors
Immunity
(2009)Transcriptional regulation of mouse L-selectin
Biochim. Biophys. Acta
(2009)An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance
Immunity
(2009)Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival
Immunity
(2004)Regulation of the interleukin-7 receptor alpha promoter by the Ets transcription factors PU.1 and GA-binding protein in developing B cells
J. Biol. Chem.
(2007)Regulatory T cells and immune tolerance
Cell
(2008)Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a
Immunity
(2004)