A critical role for the autophagy gene Atg5 in T cell survival and proliferation
Open accessAbstract
Macroautophagy (hereafter referred to as autophagy) is a well-conserved intracellular degradation process. Recent studies examining cells lacking the autophagy genes Atg5 and Atg7 have demonstrated that autophagy plays essential roles in cell survival during starvation, in innate cell clearance of microbial pathogens, and in neural cell maintenance. However, the role of autophagy in T lymphocyte development and survival is not known. Here, we demonstrate that autophagosomes form in primary mouse T lymphocytes. By generating Atg5−/− chimeric mice, we found that Atg5-deficient T lymphocytes underwent full maturation. However, the numbers of total thymocytes and peripheral T and B lymphocytes were reduced in Atg5 chimeras. In the periphery, Atg5−/− CD8+ T lymphocytes displayed dramatically increased cell death. Furthermore, Atg5−/− CD4+ and CD8+ T cells failed to undergo efficient proliferation after TCR stimulation. These results demonstrate a critical role for Atg5 in multiple aspects of lymphocyte development and function and suggest that autophagy may be essential for both T lymphocyte survival and proliferation.
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Some immune cell types such as dendritic cells seem to tolerate loss of autophagy fairly well, whereas others such as T and B cells are compromised in their development and function after autophagy inhibition.
“In this respect it is noteworthy that some cell-types of the immune system such as dendritic cells 260 seem to tolerate loss of autophagy fairly well, whereas others such as T and B cells are compromised in their development and function after autophagy inhibition.757,758”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [757]
The Abstract and Results and Discussion (pages not provided) report reduced peripheral T- and B-cell numbers in Atg5-deficient chimeras and impaired T-cell proliferation, supporting developmental and functional compromise in lymphocytes. The paper does not show impaired B-cell function; it also reports that Atg5-deficient T cells underwent full maturation. The dendritic-cell comparison has a separate citation in the citing sentence and is not attributed to this paper. (LLM, conf=0.86)
Experimental — accuracy not yet measuredProper induction of autophagy is important for maintenance of cellular bioenergetics and sustained T cell viability after activation.
“Proper induction of autophagy has been shown to be important for the maintenance of cellular bioenergetics and sustained T cell viability after activation (25, 26).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [26]
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“However, although the inhibition of autophagy can increase T-cell survival in vitro following growth factor withdrawal, it appears that T-cell survival, proliferation, and effector function in vivo is significantly impaired in the absence of autophagy (164, 165).”
BackgroundInnate and Adaptive Immunity through Autophagy
Schmid, D., & Münz, C. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.004 · Cited by 461 · see citing works
“Atg5 deficiency leads to decreased T and B cell numbers in mice, and both CD4 + and CD8 + T cells fail to undergo efficient proliferation upon T cell receptor stimulation (Pua et al., 2007) .”
BackgroundAutophagy Is Essential for Mitochondrial Clearance in Mature T Lymphocytes
Pua, H. H., Guo, J., Komatsu, M., & He, Y.-W. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0801143 · Cited by 424 · see citing works
“with our previous data (35), demonstrate that deletion of Atg5 or”
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“In contrast, most in vivo studies of autophagy, including the present one, support its role as a survival mechanism (28): the ablation of Atg5 (29) or Atg7 (21) caused cell death in neurons, and Atg5 BM chimeras showed increased susceptibility to death in T cells (30).”
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Autophagy in the renewal, differentiation and homeostasis of immune cells
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Autophagy in immunity and cell‐autonomous defense against intracellular microbes
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“Some immune cells are more dependent on autophagy, such as T cells (83, 84).”
BackgroundAutophagy is a critical regulator of memory CD8+ T cell formation
Puleston, D. J., Zhang, H., Powell, T. J., Lipina, E., Sims, S., Panse, I., Watson, A. S., Cerundolo, V., Townsend, A. R., Klenerman, P., et al. (2014) · eLife · doi:10.7554/elife.03706 · Cited by 360 · see citing works
“Previous reports have noted a number of changes to the naïve CD8+ T cell compartment in the absence of autophagy, with T cell lymphopenia, a consistent observation (Pua et al., 2007; Puleston and Simon, 2014).”
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“Evidence from Atg5 mice demonstrates that CD4 and CD8 T cell development is compromised (295, 296).”
BackgroundAutophagy and the Immune System
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“Moreover, unlike Atg5-deficient T lymphocytes, which fail to proliferate and display increased cell death, Beclin-1-deficient T lymphocytes proliferate normally (Pua et al., 2007; Arsov et al., 2011).”
BackgroundSelf-citationActivating autophagy to potentiate immunogenic chemotherapy and radiation therapy
Galluzzi, L., Bravo-San Pedro, J. M., Demaria, S., Formenti, S. C., & Kroemer, G. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.183 · Cited by 314 · see citing works
The autophagy gene <i>ATG5</i> plays an essential role in B lymphocyte development
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Metabolism in T cell activation and differentiation
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“have shown that autophagy is essential for T cell survival and proliferation [40].”
BackgroundAutophagy in Ovarian Follicular Development and Atresia
Zhou, J., Peng, X., & Mei, S. (2019) · International Journal of Biological Sciences · doi:10.7150/ijbs.30369 · Cited by 310 · see citing works
“Furthermore, the induction of autophagy in GCs has been found to be closely related to the onset of apoptosis in a model of follicular development where pregnant mare serum gonadotropin (PMSG) were primed in rat ovaries [97].”
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“For instance, while the accumulation of ubiquitin positive protein aggregates in inclusion bodies are prominent features in Atg5 and Atg7 deficient neurons and cardiomyocytes, these changes are not observed in T lymphocytes or dendritic cells that lack Atg5 expression [10; 11; 14; 22; 23].”
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FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells
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“Recent work demonstrates that T cells require autophagy during clonal expansion (29), presumably due to acute bioenergetic stress or damaged organelles encountered during high-rate cell division (21).”
BackgroundResultInfluentialAutophagy and disease: always two sides to a problem
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“The decreased survival of ATG5deleted T cells was caused by the accumulation of abnormal autophagic structures and dysregulation ofmitochondrial and ER homeostasis (25).”
BackgroundAutophagy and its role in MHC-mediated antigen presentation
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“Studies of T cells deficient in Atg5 revealed defects in cellular proliferation and survival (70), suggesting further analysis of the role of this gene product in regulating T cell responses as well as the thymic microenvironment”
BackgroundRecessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy
Cullup, T., Kho, A. L., Dionisi‐Vici, C., Brandmeier, B., Smith, F., Urry, Z., Simpson, M. A., Yau, S., Bertini, E., McClelland, V. M., et al. (2012) · Nature Genetics · doi:10.1038/ng.2497 · Cited by 282 · see citing works
“As indicated by observations in the T-cell specific atg5−/− knockout mouse, autophagy is also directly important for T-cell survival and proliferation 47 , whilst our findings also indicate a role of autophagy in B-cell homeostasis.”
Macroautophagy Regulates Energy Metabolism during Effector T Cell Activation
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“For example, Atg5 CD8 T lymphocytes display dramatically increased cell death, and Atg5 CD4 and CD8 T cells fail to undergo efficient proliferation after T-cell receptor stimulation (Pua et al., 2007).”
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p65/RelA Modulates BECN1 Transcription and Autophagy
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“Notably, the ability of anti-CD3 to induce autophagy in primary T cells has already been demonstrated (45).”
BackgroundInfluentialIL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis
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“Vps34 is involved in autophagy, a process that has been shown to be important for T cell survival [72].”
BackgroundRole of metabolism in neurodegenerative disorders
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Inflammation, ER Stress, Autophagy and MCP-1/CCR2 Pathway
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Eating the enemy within: autophagy in infectious diseases
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“Peripheral lymphocyte survival and proliferation in response to T-cell receptor (TCR) activation is decreased in atg5 / bone marrow chimera mice.(34) In addition, autophagy is induced by TCR activation in CD4þ T cells, but promotes cell death after growth factor removal.”
BackgroundThe Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
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Autophagy Signaling Through Reactive Oxygen Species
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“Furthermore, mice with Atg5 deficiency display impaired growth and maturation of T and B lymphocytes, implicating autophagy in lymphocytic proliferation and development (100, 126).”
Selective Autophagy Regulates Cell Cycle in Cancer Therapy
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Autophagy Regulates Endoplasmic Reticulum Homeostasis and Calcium Mobilization in T Lymphocytes
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“Our previous studies have demonstrated that autophagosome forms in mouse primary T lymphocytes and TCR stimulation promotes autophagy processing (25).”
BackgroundResultInfluentialSelf-citationAutophagy promotes T-cell survival through degradation of proteins of the cell death machinery
Kovács, J., Li, C., Yang, Q., Li, G., García, I., Ju, S., Roodman, D., Windle, J. J., Zhang, X., & Lu, B. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.78 · Cited by 218 · see citing works
“These data are in line with previous reports that autophagy blockade negatively affect peripheral T-cell homeostasis.(16,17) To examine the role of autophagy in T-cell survival during T-cell clonal expansion, we stimulated CD4þ T cells from both WT and 4cre BECN1 fl/fl spleens for 72 h and quantified the percent of li…”
BackgroundResultInfluentialAutophagy in nonalcoholic steatohepatitis
Amir, M., & Czaja, M. J. (2011) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/egh.11.4 · Cited by 216 · see citing works
Apoptosis and Autophagy: Decoding Calcium Signals that Mediate Life or DeathPreprint
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“For example, T cells from atg5 knockout mice do not proliferate following ligation of the T-cell receptor, nor do they survive in the periphery (Pua et al. 2007), suggesting that autophagy is required for T-cell activation.”
BackgroundThe Role of Autophagy in Cancer
Santana-Codina, N., Mancias, J. D., & Kimmelman, A. C. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-041816-122338 · Cited by 207 · see citing works
“…for various aspects of the immune response (Dengjel et al. 2005, Hubbard et al. 2010, Jacquel et al. 2012, Kondylis et al. 2013, Lee et al. 2010, Pua et al. 2007, Ushio et al. 2011, Willinger & Flavell 2012), these data indicate that systemic autophagy inhibition does not compromise and, in…”
BackgroundSelective Autophagy of the Adaptor Protein Bcl10 Modulates T Cell Receptor Activation of NF-κB
Paul, S., Kashyap, A. K., Jia, W., He, Y.-W., & Schaefer, B. C. (2012) · Immunity · doi:10.1016/j.immuni.2012.04.008 · Cited by 207 · see citing works
“, 2006), that autophagy contributes to T cell survival and antigen-dependent proliferation (Pua et al., 2007), and that autophagy-deficient T cells produce more interleukin-2 (IL-2) than their wild-type counterparts (Jia et al.”
BackgroundSelf-citationThe multifaceted role of autophagy in cancer and the microenvironment
Folkerts, H., Hilgendorf, S., Vellenga, E., Bremer, E., & Wiersma, V. R. (2018) · Medicinal Research Reviews · doi:10.1002/med.21531 · Cited by 201 · see citing works
“In addition to impaired cell proliferation, CTLs from ATG5‐knockout chimeras were ~50% more apoptotic than control T-cell, and the viability of helper T-cell from Beclin‐1‐knockout mice was also strongly reduced.(278,284) Further, spontaneous apoptosis or apoptosis after TCR activation in T-cell was increased when cor…”
BackgroundSurvival of Long-Lived Plasma Cells (LLPC): Piecing Together the Puzzle
Lightman, S. M., Utley, A. T., & Lee, K. P. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00965 · Cited by 198 · see citing works
“Within the immune compartment, mature T cells rely on autophagymediated turnover of mitochondria (mitophagy) to control intracellular production of reactive oxygen species (89, 90).”
BackgroundMechanisms of Hypoxia-Mediated Immune Escape in Cancer
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Temporal Regulation of Intracellular Organelle Homeostasis in T Lymphocytes by Autophagy
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“Together with our previous findings in Atg7Lck-Cre mice (20) and Atg5 knockout fetal liver transfer experiments (25), these results are”
BackgroundResultInfluentialSelf-citationAutophagy in health and disease. 1. Regulation and significance of autophagy: an overview
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Coronavirus Replication Does Not Require the Autophagy GeneATG5
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Self-citationInflammatory cause of metabolic syndrome via brain stress and NF-κB
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“Under normal growth conditions, autophagy occurs at a basal level to support cell growth, development and differentiation [111-117].”
BackgroundMechanisms of mitochondria and autophagy crosstalk
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Inflammasome-Independent Modulation of Cytokine Response by Autophagy in Human Cells
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“es [12,13].”
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Autophagy for tissue homeostasis and neuroprotection
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“Pancreas acinar cells Atg5 EL-I Resistance to acute pancreatitis [34] Small intestine Atg5, Atg7 Villin Paneth cell dysfunction [38 ] T cells Atg5, Atg7 Lck T-cell lymphopenia, damaged mitochondria accumulation, apoptosis increase [40,41]”
BackgroundRegulation of autophagy in mammals and its interplay with apoptosis
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“to undergo efficient proliferation after TCR stimulation [50].”
Background
- Authors
- Pua, H. H., Dzhagalov, I., Chuck, M., Mizushima, N., & He, Y.-W.
- Affiliations
- Duke Medical Center (US)
- Japan Science and Technology Agency (JP)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2006-12-26
- Volume
- 204
- Issue
- 1
- Pages
- 25-31
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118420
- OpenAlex
- W2154663531
- Cited by
- 622
- References
- 29
- Citations by year
- 2026: 10 · 2025: 23 · 2024: 17 · 2023: 23 · 2022: 25 · 2021: 31 · 2020: 34 · 2019: 35 · 2018: 34 · 2017: 39 · 2016: 45 · 2015: 35 · 2014: 34 · 2013: 42 · 2012: 55
- FWCI
- 19.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA092123, CA92123)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- autophagy, ATG5, ATG7, T cell proliferation, T cell development, autophagosomes, CD8+ T cells, CD4+ T cells, T cell receptor stimulation, lymphocyte apoptosis, chimeric mice
- MeSH terms
- Autophagy-Related Protein 5, Animals, Autophagy, Base Sequence, Cell Differentiation, Cell Survival, Female, Mice, Inbred C57BL, Microtubule-Associated Proteins, Pregnancy, Receptors, Antigen, T-Cell, T-Lymphocytes, Fetal Tissue Transplantation, DNA Primers, Transplantation Chimera, Mice, Knockout, Hematopoietic Stem Cell Transplantation, CD8-Positive T-Lymphocytes, Cell Proliferation, Mice
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