Transcription Factor Foxo1 Is a Negative Regulator of Natural Killer Cell Maturation and Function

Deng, Yihui; Kerdiles, Yann M.; Chu, Jianhong; Yuan, Shunzong; Wang, Youwei; Chen, Xilin; Mao, Hsiaoyin; Zhang, Lingling; Zhang, Jianying; Hughes, Tiffany; Deng, Yafei; Zhang, Qi; Wang, Fangjie; Zou, Xinying; Liu, Chang Gong; Freud, Aharon G.; Li, Xiaohui; Caligiuri, Michael A.; Vivier, Éric; Yu, Jianhua

doi:10.1016/j.immuni.2015.02.006

Cited by 152 publications

(191 citation statements)

References 48 publications

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“…Thus, the reduced expression of T-bet observed in NKp46-Cre-Gata3 fl/fl mice might be responsible for the migratory defect of NK cells. Similarly, Foxo1, a negative regulator in the late stage of NK cell maturation, represses T-bet (66). Unfortunately, we could not evaluate the expression of S1P5 on NK cells due to the lack of available good Abs.…”

Section: Discussionmentioning

confidence: 99%

NK Cell–Specific Gata3 Ablation Identifies the Maturation Program Required for Bone Marrow Exit and Control of Proliferation

Ali

Vivier

et al. 2016

The Journal of Immunology

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NK cells are innate lymphocytes capable of eliciting an innate immune response to pathogens. NK cells develop and become mature in the bone marrow (BM) before they migrate out to peripheral organs. Although the developmental program leading to mature NK cells has been studied in the context of several transcription factors, the stage-specific role of GATA3 in NK cell development has been incompletely understood. Using NKp46-Cre-Gata3fl/fl mice in which Gata3 deficiency was induced as early as the immature stage of NK cell differentiation, we demonstrated that GATA3 is required for the NK cell maturation beyond the CD27 single-positive stage and is indispensable for the maintenance of liver-resident NK cells. The frequencies of NK cells from NKp46-Cre-Gata3fl/fl mice were found higher in the BM but lower in peripheral organs compared with control littermates, indicating that GATA3 controls the maturation program required for BM egress. Despite the defect in maturation, upon murine CMV infection, NK cells from NKp46-Cre-Gata3fl/fl mice expanded vigorously, achieving NK cell frequencies surpassing those in controls and therefore provided comparable protection. The heightened proliferation of NK cells from NKp46-Cre-Gata3fl/fl mice was cell intrinsic and associated with enhanced upregulation of CD25 expression. Taken together, our results demonstrate that GATA3 is a critical regulator for NK cell terminal maturation and egress out of the BM and that immature NK cells present in the periphery of NKp46-Cre-Gata3fl/fl mice can rapidly expand and provide a reservoir of NK cells capable of mounting an efficient cytotoxic response upon virus infection.

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Section: Discussionmentioning

confidence: 99%

NK Cell–Specific Gata3 Ablation Identifies the Maturation Program Required for Bone Marrow Exit and Control of Proliferation

Ali

Vivier

et al. 2016

The Journal of Immunology

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“…Quantitative PCR was performed using either predesigned TaqMan probes or primers with SYBR Green Master Mix (Life Technologies) using a ViiA 7 real-time PCR system (Life Technologies). Tbx21, Eomes, and Gapdh (internal control) SYBR Green primers were obtained from Sigma-Aldrich as previously described (62), and microRNA-29b…”

Section: Author Contributionsmentioning

confidence: 99%

MicroRNA-29b mediates altered innate immune development in acute leukemia

Mundy-Bosse¹,

Scoville²,

Chen³

et al. 2016

Journal of Clinical Investigation

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“…The rational for this study was threefold: (i) KLF2 maintains homeostasis in other lymphocyte compartments, including quiescent B (11-13) and T cells (14,15); (ii) NK cell proliferation is regulated by a P13K-PDK1-Akt-mTOR signaling pathway (9,(16)(17)(18), which terminates KLF2 expression in other lymphocyte populations (19, 20; and (iii) Foxo1, which regulates Klf2 transcription in T cells (21,22), inhibits late stage NK cell differentiation (23). Based on these reports, we predicted that Klf2 gene-targeted mice would exhibit mature NK cell hyperplasia because of dysregulated proliferation and relaxed maturation checkpoints.…”

Section: Cd11bmentioning

confidence: 99%

“…Surprisingly, Foxo1, which is negatively regulated by PI3K signaling and directly promotes Klf2 transcription in T cells (21,22), does not appear to link PI3K-mediated activating events with KLF2 expression in NK cells. This disconnect between transcription factors is evidenced by an inverse expression pattern (in contrast to KLF2, Foxo1 expression decreases from stage 1→stage 3) and increased frequencies of CD27 − CD11b + NK cells in Foxo1 gene-targeted animals (23). This heretofore association between these two molecules raises the question as to what factors directly promote Klf2 transcription in NK cells.…”

Section: Cd11bmentioning

confidence: 99%

Transcription factor KLF2 regulates homeostatic NK cell proliferation and survival

Rabacal

Kumar

Hoek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells are innate lymphocytes that recognize and lyse virally infected or transformed cells. This latter property is being pursued in clinics to treat leukemia with the hope that further breakthroughs in NK cell biology can extend treatments to other cancers. At issue is the ability to expand transferred NK cells and prolong their functionality within the context of a tumor. In terms of NK cell expansion and survival, we now report that Kruppel-like factor 2 (KLF2) is a key transcription factor that underpins both of these events. Excision of Klf2 using gene-targeted mouse models promotes spontaneous proliferation of immature NK cells in peripheral tissues, a phenotype that is replicated under ex vivo conditions. Moreover, KLF2 imprints a homeostatic migration pattern on mature NK cells that allows these cells to access IL-15-rich microenvironments. KLF2 accomplishes this feat within the mature NK cell lineage via regulation of a subset of homing receptors that respond to homeostatic ligands while leaving constitutively expressed receptors that recognize inflammatory cytokines unperturbed. Under steady-state conditions, KLF2-deficient NK cells alter their expression of homeostatic homing receptors and subsequently undergo apoptosis due to IL-15 starvation. This novel mechanism has implications regarding NK cell contraction following the termination of immune responses including the possibility that retention of an IL-15 transpresenting support system is key to extending NK cell activity in a tumor environment.NK cell | KLF2 | NK cell proliferation | NK cell homeostasis | IL-15

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Transcription Factor Foxo1 Is a Negative Regulator of Natural Killer Cell Maturation and Function

Cited by 152 publications

References 48 publications

NK Cell–Specific Gata3 Ablation Identifies the Maturation Program Required for Bone Marrow Exit and Control of Proliferation

NK Cell–Specific Gata3 Ablation Identifies the Maturation Program Required for Bone Marrow Exit and Control of Proliferation

MicroRNA-29b mediates altered innate immune development in acute leukemia

Transcription factor KLF2 regulates homeostatic NK cell proliferation and survival

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