Yann M. Kerdiles

Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor

Foxo transcription factors have a conserved role in the adaptation of cells and organisms to nutrient and growth factor availability. Here we show that Foxo1 has a crucial, nonredundant role in T cells. In naive T cells, Foxo1 controlled the expression of the adhesion molecule L-selectin, the chemokine receptor CCR7 and the transcription factor Klf2, and its deletion was sufficient to alter lymphocyte trafficking. Furthermore, Foxo1 deficiency resulted in a severe defect in interleukin 7 receptor α-chain (IL-7Rα) expression associated with its ability to bind an Il7r enhancer. Finally, growth factor withdrawal induced a Foxo1-dependent increase in Sell, Klf2 and Il7r expression. These data suggest that Foxo1 regulates the homeostasis and life span of naive T cells by sensing growth factor availability and regulating homing and survival signals.

Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells

Foxo transcription factors regulate cell cycle progression, cell survival and DNA-repair pathways. Here we demonstrate that deficiency in Foxo3 resulted in greater expansion of T cell populations after viral infection. This exaggerated expansion was not T cell intrinsic. Instead, it was caused by the enhanced capacity of Foxo3-deficient dendritic cells to sustain T cell viability by producing more interleukin 6. Stimulation of dendritic cells mediated by the coinhibitory molecule CTLA-4 induced nuclear localization of Foxo3, which in turn inhibited the production of interleukin 6 and tumor necrosis factor. Thus, Foxo3 acts to constrain the production of key inflammatory cytokines by dendritic cells and to control T cell survival.

The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice

A key adaptation to environmental hypoxia is an increase in erythropoiesis, driven by the hormone erythropoietin (EPO) through what is traditionally thought to be primarily a renal response. However, both neurons and astrocytes (the largest subpopulation of glial cells in the CNS) also express EPO following ischemic injury, and this response is known to ameliorate damage to the brain. To investigate the role of glial cells as a component of the systemic response to hypoxia, we created astrocyte-specific deletions of the murine genes encoding the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha and their negative regulator von Hippel-Lindau (VHL) as well as astrocyte-specific deletion of the HIF target gene Vegf. We found that loss of the hypoxic response in astrocytes does not cause anemia in mice but is necessary for approximately 50% of the acute erythropoietic response to hypoxic stress. In accord with this, erythroid progenitor cells and reticulocytes were substantially reduced in number in mice lacking HIF function in astrocytes following hypoxic stress. Thus, we have demonstrated that the glial component of the CNS is an essential component of hypoxia-induced erythropoiesis.

Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

Tissue injury initiates a complex series of events that act to restore structure and physiological homeostasis. Infiltration of inflammatory cells and vascular remodeling are both keystones of this process. However, the role of inflammation and angiogenesis in general and, more specifically, the significance of inflammatory cell-derived VEGF in this context are unclear. To determine the role of inflammatory cell-derived VEGF in a clinically relevant and chronically inflamed injury, pulmonary fibrosis, we deleted the VEGF-A gene in myeloid cells. In a model of pulmonary fibrosis in mice, deletion of VEGF in myeloid cells resulted in significantly reduced formation of blood vessels; however, it causes aggravated fibrotic tissue damage. This was accompanied by a pronounced decrease in epithelial cell survival and a striking increase in myofibroblast invasion. The drastic increase in fibrosis following loss of myeloid VEGF in the damaged lungs was also marked by increased levels of hypoxia-inducible factor (HIF) expression and Wnt/β-catenin signaling. This demonstrates that the process of angiogenesis, driven by myeloid cell-derived VEGF, is essential for the prevention of fibrotic damage.

Highly specialized role of Forkhead box O transcription factors in the immune system.

Recent studies have highlighted a fundamental role for Forkhead box O (Foxo) transcription factors in immune system homeostasis. Initial reports designed to dissect function of individual Foxo isoforms in the immune system were based on in vitro overexpression systems, and these experiments suggested that Foxo1 and Foxo3 are important for growth factor withdrawal-induced cell death. Moreover, Foxo factors importantly regulate basic cell cycle progression, and so the implication was that these factors may control lymphocyte homeostasis, including a critical function in the termination and resolution of an immune response. Most recently, cell-type-specific loss mutants for the different Foxo isoforms have revealed unexpected and highly specialized functions in the control of multiple cell types in the immune system, but they have yet to reveal a role in cell death or proliferation. This review will focus on the recent advances made in the understanding of the many ways that Foxo factors regulate the immune system, including a discussion of how the specialized versus redundant functions of Foxo transcription factors impact immune system homeostasis.

Abstract A10: The hypoxic response in natural killer cells: Linking cytoxicity and tumor immune surveillance to angiogenesis

Hypoxia-inducible transcription factors (HIFs) are central mediators of cellular adaptation to low oxygen and play a pivotal role in inflammatory responses. Natural Killer (NK) cells, unifying characteristics of innate and adaptive immunity, are cytotoxic innate lymphoid cells with a unique ability to instantly recognize and kill “aberrant” cancer cells while sparing “normal” cells. Owing to these tumoricidal features, NK cells are able to restrict primary tumor growth and limit metastatic spread. By genetic targeting HIFs in NK cells HIFs, we define a crucial role of HIF-1 in NK cell function and cancer immune surveillance. We show that NK cells preferentially infiltrate into hypoxic zones of solid primary tumors and that HIF-1-deficiency in NK cells slows impairs primary tumor growth as well as distant metastasis. This is due to reduced susceptibility of HIF-1-deficient NK cells to tumor cell-derived inhibitory stimuli, resulting in improved recognition and killing of tumor cells. Furthermore, we define the hypoxic response in NK cells as a critical mediator of tumor angiogenesis. Paradoxically, HIF-1-deficiency in NK cells results in decreased expression of various angiostatic factors within the tumor microenvironment, resulting in unproductive tumor angiogenesis, characterized by immature, non-functional vessel and severe tumor hypoxia. This suggests that the hypoxic response in NK cells slows down overall tumor angiogenesis in order to allow for vessel formation in a more coordinated fashion. In summary, we define HIF-1 as a critical mediator of NK cell effector function and cancer immune surveillance. Secondly, we show that HIF-1 in NK cells acts as a negative regulator of tumor angiogenesis that ensures the fine-tuning of the angiogenic response. These results indicate that exploiting the hypoxic response in NK cells may represent a novel therapeutic avenue. Citation Format: Ewelina Krzywinska, Chahrazade Kantari-Mimoun, Magali Castells, Dagmar Gotthardt, Yann Kerdiles, Ralph Klose, Joachim Fandrey, Veronika Sexl, Christian Stockmann. The hypoxic response in natural killer cells: Linking cytoxicity and tumor immune surveillance to angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A10.