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.
"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. "
"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   . A core set of transcription factors such as Blimp1, Eomes, T-bet, IKZF, and Foxo can distinguish these T cell subsets (Table 1). "
[Show abstract][Hide abstract] 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.
"Cytokine production by FoxO1 fl/fl CTLs was only modestly affected, but the expression of granzyme B, a FoxO1-repressed target gene (Macintyre et al., 2011; Hess Michelini et al., 2013; Rao et al., 2012; Tejera et al., 2013), was markedly increased (Figures 5C, 5D, and S3B). Despite this, viral loads remained significantly higher in FoxO1 fl/fl relative to FoxO1 +/+ mice, probably owing to a combination of decreased proliferation and survival of LCMVspecific CTLs in the absence of FoxO1 as suggested by Ki67 and by the ratio of Bim to Bcl-2 staining, respectively (Figures 5E–5G and S3C; Kim et al., 2013; Tejera et al., 2013). Taken together, these data propose an intriguing model wherein the suppression of mTOR and AKT, and resulting increase in "
Ana Paula Duarte de Souza, Deise Nascimento de Freitas, Krist Elen Antuntes Fernandes, Mariana D'Avila da Cunha, Jheini Lis Antunes Fernandes, Rodrigo Benetti Gassen, Tiago Fazolo, Leonardo A Pinto, Marcelo Scotta, Rita Mattiello, Paulo M Pitrez, Cristina Bonorino, Renato T Stein
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