Autophagy-related protein PIK3C3/VPS34 controls T cell metabolism and function

Yang, Guan; Song, Wenqiang; Postoak, J. Luke; Chen, Jin; Martinez, Jennifer; Zhang, Jianhua; Wu, Lan; Kaer, Luc Van

doi:10.1080/15548627.2020.1752979

Cited by 58 publications

(45 citation statements)

References 44 publications

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“…Several research groups including our own found that inhibition of autophagy in T cells protects mice from EAE development. Mice with T cell-specific ablation of Pik3c3 or Becn1 failed to mount autoimmune responses and were completely resistant to active EAE induction ( 28 , 29 ). Mechanistically, these animals exhibited severely impaired MOG-reactive T helper (Th)1 and Th17 responses.…”

Section: Autophagy Manipulation In Immune Cells Alters Eae Pathogenesismentioning

confidence: 99%

“…T cells from the latter animals were hyporesponsive to antigenic stimulation and failed to accumulate in the spinal cord following EAE induction ( 30 ). To exclude effects mediated by defective T cell development, we adoptively transferred tamoxifen-treated splenic T cells derived from MOG 35-55 -immunized pik3c3 f/f ;Rosa26-CreER T2 mice (the Pik3c3 gene in these animals can be temporally deleted by treatment with tamoxifen, which binds to the estrogen receptor [ER] T2 to release Cre recombinase from the cytoplasm to the nucleus) at 10 days after immunization to wild-type (WT) animals, resulting in profoundly impaired EAE ( 29 ). Together, these results provide evidence that T cell autophagy is required to establish efficient T cell responses and to break tolerance against CNS antigens during EAE.…”

Section: Autophagy Manipulation In Immune Cells Alters Eae Pathogenesismentioning

confidence: 99%

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Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?

Yang

Kaer

2021

Front. Immunol.

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding nerve fibers that project from neurons. The pathological hallmark of MS is multiple areas of myelin loss accompanied by inflammation within the CNS, resulting in loss of cognitive function that ultimately leads to paralysis. Recent studies in MS have focused on autophagy, a cellular self-eating process, as a potential target for MS treatment. Here, we review the contribution of immune cell autophagy to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the prototypic animal model of MS. A better understanding of the role of autophagy in different immune cells to EAE might inform the development of novel therapeutic approaches in MS and other autoimmune and inflammatory diseases.

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Section: Autophagy Manipulation In Immune Cells Alters Eae Pathogenesismentioning

confidence: 99%

Section: Autophagy Manipulation In Immune Cells Alters Eae Pathogenesismentioning

confidence: 99%

Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?

Yang

Kaer

2021

Front. Immunol.

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“…A high level of IL‐4 and IL‐13 is beneficial for T H 2 differentiation and these cytokines inhibit T H 1 and T reg differentiation in ATG16L1 fl/fl CD4 cre mice 21 . In PIK3C3‐Vps34 knockout mice, the autophagy‐defective CD4 + T cells lose their capacity to differentiate into T H 1 subsets and this is associated with a reduction of the mitochondrial activity caused by dysfunctional autophagy 33 . The sharp decrease of IFN‐γ in autophagy‐deficient T H 1 reveals its lower differentiation ability 33 .…”

Section: Autophagy Modulates T Cell Differentiationmentioning

confidence: 99%

“…In PIK3C3‐Vps34 knockout mice, the autophagy‐defective CD4 + T cells lose their capacity to differentiate into T H 1 subsets and this is associated with a reduction of the mitochondrial activity caused by dysfunctional autophagy 33 . The sharp decrease of IFN‐γ in autophagy‐deficient T H 1 reveals its lower differentiation ability 33 . The autophagy blockade CD4 + T cells boosts T H 9 cell differentiation and autophagy‐deficient T H 9 increases IL‐9 secretion 34 .…”

Section: Autophagy Modulates T Cell Differentiationmentioning

confidence: 99%

“…IL‐21 is known to target the mTOR pathway and to suppress autophagy, thereby impairing T reg cell function 31 . In experimental autoimmune encephalomyelitis, mice with conditional autophagy‐deficient ( Beclin‐1 or PIK3C3‐Vps34 ) CD4 + T cells were resistant to disease 32,33 . Mice with deletion of the pro‐autophagy protein, Ambra1, suffered from a loss of the T reg population and deterioration of the disease 30 .…”

Section: Altered Autophagy In T Cells and Inflammation Autoimmune DImentioning

confidence: 99%

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Autophagy in T‐cell differentiation, survival and memory

Wang

Das

Kumar

et al. 2020

Immunol. Cell Biol.

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Over the past decade, autophagy has emerged as a critical regulatory mechanism of the immune system through critically controlling various aspects of T cell biology and determining the fate of different T cell subsets. Autophagy maintains T cell development and survival by regulating the degradation of organelles and apoptotic proteins. The autophagic process also impacts the formation of memory T cells. Alteration of autophagy in T cells may lead to a variety of pathological conditions such as inflammation, autoimmune diseases and cancer. In this review, we discuss how autophagy impacts T cell differentiation, survival and memory, and its implication in immunotherapy for various diseases.

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Dual Activity of Type III PI3K Kinase Vps34 is Critical for NK Cell Development and Senescence

Chen,

Li,

Feng

et al. 2024

Advanced Science

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Vps34 is the unique member of the class III phosphoinositide 3‐kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this study, a model without Vps34 (Vps34fl/fl/CD122Cre/+) is generated, deleting Vps34 during and after NK‐cell commitment. These mice exhibit a nearly 90% decrease in NK cell count and impaired differentiation. A mechanistic study reveals that the absence of Vps34 disrupts the transport of IL‐15 receptor subunit alpha CD122 to the cell membrane, resulting in reduced responsiveness of NK cells to IL‐15. In mice lacking Vps34 at the terminal stage of NK‐cell development (Vps34fl/fl/Ncr1Cre/+), NK cells gradually diminish during aging. This phenotype is associated with autophagy deficiency and the stress induced by reactive oxygen species (ROS). Therefore, terminally differentiated NK cells lacking Vps34 display an accelerated senescence phenotype, while the application of antioxidants effectively reverses the senescence caused by Vps34 deletion by neutralizing ROS. In summary, this study unveils the dual and unique activity of Vps34 in NK cells. Vps34‐mediated vesicular transport is crucial for CD122 membrane trafficking during NK cell commitment, whereas Vps34‐mediated autophagy can delay NK cell senescence.

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Autophagy-related protein PIK3C3/VPS34 controls T cell metabolism and function

Cited by 58 publications

References 44 publications

Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?

Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?

Autophagy in T‐cell differentiation, survival and memory

Dual Activity of Type III PI3K Kinase Vps34 is Critical for NK Cell Development and Senescence

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