The Transcription Factor Foxo1 Controls Central-Memory CD8+ T Cell Responses to Infection

Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Immunity (Impact Factor: 21.56). 08/2013; 39(2). DOI: 10.1016/j.immuni.2013.07.013
Source: PubMed


Memory T cells protect hosts from pathogen reinfection, but how these cells emerge from a pool of antigen-experienced T cells is unclear. Here, we show that mice lacking the transcription factor Foxo1 in activated CD8(+) T cells have defective secondary, but not primary, responses to Listeria monocytogenes infection. Compared to short-lived effector T cells, memory-precursor T cells expressed higher amounts of Foxo1, which promoted their generation and maintenance. Chromatin immunoprecipitation sequencing revealed the transcription factor Tcf7 and the chemokine receptor Ccr7 as Foxo1-bound target genes, which have critical functions in central-memory T cell differentiation and trafficking. These findings demonstrate that Foxo1 is selectively incorporated into the genetic program that regulates memory CD8(+) T cell responses to infection.

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    • "In the absence of mTORC2, increased Foxo1 retention in the nucleus of CD8 T cells drives enhanced Eomes and Tcf-1 expression, which promotes CD8 memory differentiation (Figure 7H). Indeed, Foxo1 directly induced expression of both Eomes and Tcf-1, as shown by chromatin immunoprecipitation sequencing experiments (Hess Michelini et al., 2013;Kim et al., 2013;Rao et al., 2012;Tejera et al., 2013). Moreover, it is known that Foxo1 acts as a repressor of T-bet expression in CD8 T cells (Rao et al., 2012). "
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    ABSTRACT: Upon infection, antigen-specific naive CD8 T cells are activated and differentiate into short-lived effector cells (SLECs) and memory precursor cells (MPECs). The underlying signaling pathways remain largely unresolved. We show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2), regulates SLEC and MPEC commitment. Rictor deficiency favors memory formation and increases IL-2 secretion capacity without dampening effector functions. Moreover, mTORC2-deficient memory T cells mount more potent recall responses. Enhanced memory formation in the absence of mTORC2 was associated with Eomes and Tcf-1 upregulation, repression of T-bet, enhanced mitochondrial spare respiratory capacity, and fatty acid oxidation. This transcriptional and metabolic reprogramming is mainly driven by nuclear stabilization of Foxo1. Silencing of Foxo1 reversed the increased MPEC differentiation and IL-2 production and led to an impaired recall response of Rictor KO memory T cells. Therefore, mTORC2 is a critical regulator of CD8 T cell differentiation and may be an important target for immunotherapy interventions.
    Full-text · Article · Jan 2016 · Cell Reports
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    • "The latter question is important because negative regulators or checkpoints are undoubtedly involved in NK cell development or maturation, whereas all aforementioned transcription factors that have been identified as participating in this process are positive regulators. Foxos are transcription factors whose expression is associated with the generation of common lymphoid progenitors and the regulation of T cell and B cell development and function (Chow et al., 2013; Hedrick et al., 2012; Hess Michelini et al., 2013; Kim et al., 2013; Ouyang et al., 2012; Staron et al., 2014; Togher et al., 2015). Some of these elegant studies also demonstrate that Foxo1 and Foxo3 regulate their target genes in a highly cell-and context-specific mechanism. "
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    ABSTRACT: Little is known about the role of negative regulators in controlling natural killer (NK) cell development and effector functions. Foxo1 is a multifunctional transcription factor of the forkhead family. Using a mouse model of conditional deletion in NK cells, we found that Foxo1 negatively controlled NK cell differentiation and function. Immature NK cells expressed abundant Foxo1 and little Tbx21 relative to mature NK cells, but these two transcription factors reversed their expression as NK cells proceeded through development. Foxo1 promoted NK cell homing to lymph nodes by upregulating CD62L expression and inhibited late-stage maturation and effector functions by repressing Tbx21 expression. Loss of Foxo1 rescued the defect in late-stage NK cell maturation in heterozygous Tbx21(+/-) mice. Collectively, our data reveal a regulatory pathway by which the negative regulator Foxo1 and the positive regulator Tbx21 play opposing roles in controlling NK cell development and effector functions. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Immunity
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    • "However, kinetics of calcium signaling, constitutive MAPK and ERK signaling pathways could be distinctive features of exhaustion. The gene transcription profiles of exhausted T cells are distinct from anergic, memory and terminally differentiated T cells [2] [12] [13]. A core set of transcription factors such as Blimp1, Eomes, T-bet, IKZF, and Foxo can distinguish these T cell subsets (Table 1). "
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    ABSTRACT: T cells reactive to tumor antigens and viral antigens lose their reactivity when exposed to the antigen-rich environment of a larger tumor bed or viral load. Such non-responsive T cells are termed exhausted. T cell exhaustion affects both CD8+ and CD4+ T cells. T cell exhaustion is attributed to the functional impairment of T cells to produce cytokines, of which the most important may be Interleukin 2 (IL2). IL2 performs functions critical for the elimination of cancer cells and virus infected cells. In one such function, IL2 promotes CD8+ T cell and natural killer (NK) cell cytolytic activities. Other functions include regulating naïve T cell differentiation into Th1 and Th2 subsets upon exposure to antigens. Thus, the signaling pathways contributing to T cell exhaustion could be linked to the signaling pathways contributing to IL2 loss. This review will discuss the process of T cell exhaustion and the signaling pathways that could be contributing to T cell exhaustion.
    Full-text · Article · Dec 2014 · Cytokine
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