Macroautophagy in T Lymphocyte Development and Function

He, Min; McLeod, Ian X.; Jia, Wei; He, You–Wen

doi:10.3389/fimmu.2012.00022

Cited by 26 publications

(28 citation statements)

References 62 publications

(118 reference statements)

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“…Indeed, LC3B expression is increased in CRTAM + Vg9Vd2 T cells following interaction with Necl-2-expressing tumor cells. Autophagy is characterized by an active degradation of intracellular components through the lysosomal pathway (33). In agreement with these data, our results with acridine orange show a higher accumulation of acidic vesicular organelles in Vg9Vd2 T cells after coculture with Necl-2 + tumor cells (25).…”

Section: Discussionsupporting

confidence: 81%

CRTAM Receptor Engagement by Necl-2 on Tumor Cells Triggers Cell Death of Activated Vγ9Vδ2 T Cells

Dessarthe

Thedrez

Latouche

et al. 2013

The Journal of Immunology

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Human Vγ9Vδ2 T cells exert potent in vitro and in vivo antitumor activities, making them promising candidates for immunotherapy strategies. Recognition of tumor cells by Vγ9Vδ2 T cells requires engagement of the TCR and/or NK receptors. Recently, one of the novel NK receptors, the class I–restricted T cell–associated molecule (CRTAM), has been described to promote cytotoxic function of NK cells and to lead to IFN-γ secretion by CD8+ T cells through interaction with its ligand, Necl-2. A better understanding of the role of CRTAM in Vγ9Vδ2 T cell functions is highly relevant to optimize innate-like T cell–based cancer immunotherapy. In this article, we report that CRTAM is transiently expressed on activated Vγ9Vδ2 T lymphocytes following TCR engagement. However, CRTAM–Necl-2 interaction does not modify the cytotoxic function or IFN-γ secretion of Vγ9Vδ2 T cells. The expression of CRTAM in activated Vγ9Vδ2 T cells is quickly downregulated following interaction with Necl-2 on tumor cells. Of interest, CRTAM is concurrently acquired at the cell surface of Necl-2+ tumor cells through Vγ9Vδ2 T cell membrane capture. Finally, we highlight that coculture experiments with tumor cells expressing Necl-2 result in significant cell death of CRTAM+ Vγ9Vδ2 T cells. CRTAM-mediated cell death is dependent on an autophagic process, but not on apoptosis or necroptosis, as attested by the expression of characteristic markers and blocking experiments with specific inhibitors. On the basis of these findings, we propose that Necl-2 on tumor cells represents a new tumor counterattack mechanism and a potential target to improve efficiency of γδ T cell–based immunotherapy.

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Section: Discussionsupporting

confidence: 81%

CRTAM Receptor Engagement by Necl-2 on Tumor Cells Triggers Cell Death of Activated Vγ9Vδ2 T Cells

Dessarthe

Thedrez

Latouche

et al. 2013

The Journal of Immunology

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“…9,10 Overexpression of c-FLIP suppresses autophagy, as c-FLIP competes with LC3 for Atg3 binding. 11 Moreover, recent studies suggest a correlation between caspase 8 inhibition and excessive autophagy.…”

Section: Cellular Caspase 8 (Flice)-like Inhibitory Protein (C-flip) mentioning

confidence: 99%

A role for c-FLIPL in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes

2012

Cell Death Differ

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Caspase 8 plays a dual role in the survival of T lymphocytes. Although active caspase 8 mediates apoptosis upon death receptor signaling, the loss of caspase 8 activity leads to receptor-interacting protein (RIP)-1/RIP-3-dependent necrotic cell death (necroptosis) upon TCR activation. The anti-apoptotic protein c-FLIP (cellular caspase 8 (FLICE)-like inhibitory protein) suppresses death receptor-induced caspase 8 activation. Moreover, recent findings suggest that c-FLIP is also involved in inhibiting necroptosis and autophagy. It remains unclear whether c-FLIP protects primary T lymphocytes from necroptosis or regulates the threshold at which autophagy occurs. Here, we used a c-FLIP isoform-specific conditional deletion model to show that c-FLIP L -deficient T cells underwent RIP-1-dependent necroptosis upon TCR stimulation. Interestingly, although previous studies have only described necroptosis in the absence of caspase 8 activity, we found that pro-apoptotic caspase 8 activity and apoptosis were also enhanced in c-FLIP L -deficient T lymphocytes. Furthermore, c-FLIP L -deficient T cells exhibited enhanced autophagy, which served a cytoprotective function. Together, these findings indicate that c-FLIP L plays an important antinecroptotic role and is a key regulator of apoptosis, autophagy, and necroptosis in T lymphocytes.

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“…5,6 Autophagy plays an essential role in the development and function of T lymphocytes. Autophagy regulates the calcium mobilization and energy metabolism in T cells, [7][8][9] is critical for effector CD8 + T cell survival and memory formation, 10,11 promotes the proliferation and survival of invariant NKT cells 12,13 and tunes down TCR signaling by degrading BCL10. 14 Autophagy starts with a membrane precursor called the phagophore.…”

Section: Introductionmentioning

confidence: 99%

Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1

Jia

McLeod

et al. 2015

Autophagy

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The highly conserved cellular degradation pathway, macroautophagy, regulates the homeostasis of organelles and promotes the survival of T lymphocytes. Previous results indicate that Atg3-, Atg5-, or Pik3c3/Vps34-deficient T cells cannot proliferate efficiently. Here we demonstrate that the proliferation of Atg7-deficient T cells is defective. By using an adoptive transfer and Listeria monocytogenes (LM) mouse infection model, we found that the primary immune response against LM is intrinsically impaired in autophagy-deficient CD8 + T cells because the cell population cannot expand after infection. Autophagy-deficient T cells fail to enter into S-phase after TCR stimulation. The major negative regulator of the cell cycle in T lymphocytes, CDKN1B, is accumulated in autophagy-deficient na€ ıve T cells and CDKN1B cannot be degraded after TCR stimulation. Furthermore, our results indicate that genetic deletion of one allele of CDKN1B in autophagy-deficient T cells restores proliferative capability and the cells can enter into S-phase after TCR stimulation. Finally, we found that natural CDKN1B forms polymers and is physiologically associated with the autophagy receptor protein SQSTM1/p62 (sequestosome 1). Collectively, autophagy is required for maintaining the expression level of CDKN1B in na€ ıve T cells and selectively degrades CDKN1B after TCR stimulation.

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Macroautophagy in T Lymphocyte Development and Function

Cited by 26 publications

References 62 publications

CRTAM Receptor Engagement by Necl-2 on Tumor Cells Triggers Cell Death of Activated Vγ9Vδ2 T Cells

CRTAM Receptor Engagement by Necl-2 on Tumor Cells Triggers Cell Death of Activated Vγ9Vδ2 T Cells

A role for c-FLIPL in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes

Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1

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