Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development

Park, Heon; Tsang, Mark; Iritani, Brian M.; Bevan, Michael J.

doi:10.1073/pnas.1406473111

Cited by 38 publications

(42 citation statements)

References 51 publications

(68 reference statements)

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“…Deficiency of Fnip1 led to inability to shut off mTOR mediated energy consuming cellular processes, which could inhibit autophagy. However, inhibition of mTOR was not able to rescue the defect in i NKT cells, indicating Fnip1 is required for i NKT cell development in both an mTOR-dependent and -independent manner (75), and a connection to decreased autophagy was not established in this study. While this manuscript was in revision, a study was published indicating that mice with a Atg7 deficiency driven by CD4 Cre have a reduction in i NKT cells in the thymus and periphery, consistent with the results here (76).…”

Section: Discussionmentioning

confidence: 56%

Invariant NKT Cells Require Autophagy To Coordinate Proliferation and Survival Signals during Differentiation

Peng

Zhao

Miller

et al. 2015

The Journal of Immunology

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Autophagy regulates cell differentiation, proliferation and survival in multiple cell types, including cells of the immune system. Herein we examined the effects of a disruption of autophagy on the differentiation of invariant natural killer T cells (iNKT cells). Using mice with a T lymphocyte specific deletion of Atg5 or Atg7,two members of the macroautophagic pathway, we observed a profound decrease in the iNKT cell population. The deficit is cell-autonomous, and it acts predominantly to reduce the number of mature cells, as well as the function of peripheral iNKT cells. In the absence of autophagy, there is reduced progression of iNKT cells in the thymus through the cell cycle, as well as increased apoptosis of these cells. Importantly, the reduction in Th1-biased iNKT cells is most pronounced, leading to a selective reduction in iNKT cell derived IFNγ. Our findings highlight the unique metabolic and genetic requirements for the differentiation of iNKT cells.

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Section: Discussionmentioning

confidence: 56%

Invariant NKT Cells Require Autophagy To Coordinate Proliferation and Survival Signals during Differentiation

Peng

Zhao

Miller

et al. 2015

The Journal of Immunology

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“…Other mice with mutations leading to abnormal metabolic activity, such as Fnip KO mice (11) which have reduced ATP uptake and increased ROS in NKT cells, also have defects in iNKT cell proliferation. NKT cells from PDK1 KO mice have a reduction in CD71 and CD98 surface expression (10), leading to a decreased absolute number of iNKT cells.…”

Section: Discussionmentioning

confidence: 99%

NKAP Regulates Invariant NKT Cell Proliferation and Differentiation into ROR-γt–Expressing NKT17 Cells

Thapa

Chen

McWilliams

et al. 2016

The Journal of Immunology

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Invariant Natural Killer T (iNKT) cells are a unique lineage with characteristics of both adaptive and innate lymphocytes, and recognize glycolipid presented by an MHC Class I-like CD1d molecule. During thymic development, iNKT cells also differentiate into NKT1, NKT2 and NKT17 functional subsets that preferentially produce cytokines IFN-γ, IL-4 and IL-17, respectively, upon activation. Newly selected iNKT cells undergo a burst of proliferation, which is defective in mice with a specific deletion of NKAP in the iNKT cell lineage, leading to severe reductions in thymic and peripheral iNKT cell numbers. The decreased cell number is not due to defective homeostasis or increased apoptosis, and is not rescued by Bcl-xL overexpression. NKAP is also required for differentiation into NKT17 cells, but NKT1 and NKT2 cell development and function are unaffected. This failure in NKT17 development is rescued by transgenic expression of PLZF; however, the PLZF transgene does not restore iNKT cell numbers or the block in positive selection into the iNKT cell lineage in CD4-cre NKAP cKO mice. Therefore, NKAP regulates multiple steps in iNKT cell development and differentiation.

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“…Thus, NUAK1 may play an important role to return positively selected T lymphocytes to a quiescent state. The metabolic regulator Folliculin-interacting protein 1 (Fnip1) is also crucial for iNKT and noninvariant NKT cell development (54). Residual Fnip1 −/− iNKT cells are more sensitive to apoptosis, which has been suggested to be secondary to altered mitochondrial homeostasis and metabolic stress.…”

Section: Discussionmentioning

confidence: 99%

Essential role for autophagy during invariant NKT cell development

Salio

Puleston

Mathan

et al. 2014

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

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Autophagy is an evolutionarily conserved cellular homeostatic pathway essential for development, immunity, and cell death. Although autophagy modulates MHC antigen presentation, it remains unclear whether autophagy defects impact on CD1d lipid loading and presentation to invariant natural killer T (iNKT) cells and on iNKT cell differentiation in the thymus. Furthermore, it remains unclear whether iNKT and conventional T cells have similar autophagy requirements for differentiation, survival, and/or activation. We report that, in mice with a conditional deletion of the essential autophagy gene Atg7 in the T-cell compartment (CD4 Cre-Atg7), thymic iNKT cell development-unlike conventional T-cell development-is blocked at an early stage and mature iNKT cells are absent in peripheral lymphoid organs. The defect is not due to altered loading of intracellular iNKT cell agonists; rather, it is T-cell-intrinsic, resulting in enhanced susceptibility of iNKT cells to apoptosis. We show that autophagy increases during iNKT cell thymic differentiation and that it developmentally regulates mitochondrial content through mitophagy in the thymus of mice and humans. Autophagy defects result in the intracellular accumulation of mitochondrial superoxide species and subsequent apoptotic cell death. Although autophagy-deficient conventional T cells develop normally, they show impaired peripheral survival, particularly memory CD8 + T cells. Because iNKT cells, unlike conventional T cells, differentiate into memory cells while in the thymus, our results highlight a unique autophagy-dependent metabolic regulation of adaptive and innate T cells, which is required for transition to a quiescent state after population expansion.utophagy is an evolutionarily conserved catabolic process that, by facilitating the breakdown and recycling of damaged organelles and long-lived proteins, is essential to maintaining cellular homeostasis (1). The autophagy pathway is highly regulated during development and also by environmental factors such as nutrient availability/starvation, hypoxia, and reactive oxygen species (ROS). The process is controlled by a number of autophagy-related genes (Atg) and starts with the formation of a double-membraned vesicle (the autophagosome) engulfing the cytoplasmic components to be delivered to the lysosome for degradation. Formation of the autophagosome requires the concerted action of two ubiquitin-like conjugation systems in which Atg12 is covalently linked to Atg5 and Atg8 is conjugated to phosphatidylethanolamine (2, 3). Atg7 is a necessary catalyst in both conjugation systems and is therefore essential for autophagy (3).Due to its important role in cellular homeostasis, dysregulation of autophagy has been implicated in several pathological processes, including neurodegeneration, autoimmunity, cancer, and infection (4). Furthermore, autophagy plays an important role during immune responses by regulating pathogen handling and antigen presentation (5, 6). It is well established that different populations of αβ T lymph...

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Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development

Cited by 38 publications

References 51 publications

Invariant NKT Cells Require Autophagy To Coordinate Proliferation and Survival Signals during Differentiation

Invariant NKT Cells Require Autophagy To Coordinate Proliferation and Survival Signals during Differentiation

NKAP Regulates Invariant NKT Cell Proliferation and Differentiation into ROR-γt–Expressing NKT17 Cells

Essential role for autophagy during invariant NKT cell development

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