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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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“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]
Experimental — accuracy not yet measuredIn the citing paper
“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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“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
Hubbard, V. M., Valdor, R., Patel, B., Singh, R., Cuervo, A. M., & Macian, F. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000576 · Cited by 275
Enhancing Immunity Through Autophagy
Münz, C. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132537 · Cited by 269
Therapeutic Targeting of Autophagy in Disease: Biology and Pharmacology
Cheng, Y., Ren, X., Hait, W. N., & Yang, J. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.007120 · Cited by 262
“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).”
BackgroundMeng, Q., & Cai, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.254417 · Cited by 266
p65/RelA Modulates BECN1 Transcription and Autophagy
Copetti, T., Bertoli, C., Dalla, E., Demarchi, F., & Schneider, C. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01396-08 · Cited by 262
“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
Carrette, F., & Surh, C. D. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.010 · Cited by 257
“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
Procaccini, C., Santopaolo, M., Faicchia, D., Colamatteo, A., Formisano, L., de Candia, P., Galgani, M., De Rosa, V., & Matarese, G. (2016) · Metabolism · doi:10.1016/j.metabol.2016.05.018 · Cited by 258
Kolattukudy, P. E., & Niu, J. (2012) · Circulation Research · doi:10.1161/circresaha.111.243212 · Cited by 249
Valdor, R., Mocholi, E., Botbol, Y., Guerrero-Ros, I., Chandra, D., Koga, H., Gravekamp, C., Cuervo, A. M., & Macian, F. (2014) · Nature Immunology · doi:10.1038/ni.3003 · Cited by 244
Eating the enemy within: autophagy in infectious diseases
Orvedahl, A., & Levine, B. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.130 · Cited by 241
“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
Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 236
Valcourt, J. R., Lemons, J. M. S., Haley, E. M., Kojima, M. L., Demuren, O. O., & Coller, H. A. (2012) · Cell Cycle · doi:10.4161/cc.19879 · Cited by 240
Zhang, J., Randall, M. S., Loyd, M. R., Dorsey, F. C., Kundu, M., Cleveland, J. L., & Ney, P. A. (2009) · Blood · doi:10.1182/blood-2008-04-151639 · Cited by 235
Autophagy Signaling Through Reactive Oxygen Species
Huang, J., Lam, G. Y., & Brumell, J. H. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3554 · Cited by 228
“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
Zheng, K., He, Z., Kitazato, K., & Wang, Y. (2018) · Theranostics · doi:10.7150/thno.30308 · Cited by 229
Liu, F., Fang, F., Yuan, H., Yang, D., Chen, Y., Williams, L., Goldstein, S. A., Krebsbach, P. H., & Guan, J. (2013) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1971 · Cited by 228
Autophagy Regulates Endoplasmic Reticulum Homeostasis and Calcium Mobilization in T Lymphocytes
Jia, W., Pua, H. H., Li, Q.-J., & He, Y.-W. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001822 · Cited by 224
“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 224
“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 218
Apoptosis and Autophagy: Decoding Calcium Signals that Mediate Life or DeathPreprint
Harr, M. W., & Distelhorst, C. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005579 · Cited by 217
“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 214
“…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 221
“, 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 203
“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
“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
Barsoum, I. B., Koti, M., Siemens, D. R., & Graham, C. H. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-2598 · Cited by 205
Temporal Regulation of Intracellular Organelle Homeostasis in T Lymphocytes by Autophagy
Jia, W., & He, Y.-W. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002404 · Cited by 204
“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
Mehrpour, M., Esclatine, A., Beau, I., & Codogno, P. (2010) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00507.2009 · Cited by 211
Coronavirus Replication Does Not Require the Autophagy GeneATG5
Zhao, Z., Thackray, L. B., Miller, B. C., Lynn, T. M., Becker, M. M., Ward, E., Mizushima, N., Denison, M. R., & Virgin, H. W. (2007) · Autophagy · doi:10.4161/auto.4782 · Cited by 200
Self-citationStephenson, L. M., Miller, B. C., Ng, A., Eisenberg, J. M., Zhao, Z., Cadwell, K., Graham, D. B., Mizushima, N., Xavier, R. J., Virgin, H. W., et al. (2009) · Autophagy · doi:10.4161/auto.5.5.8133 · Cited by 200
Self-citationInflammatory cause of metabolic syndrome via brain stress and NF-κB
Cai, D., & Liu, T. (2012) · Aging · doi:10.18632/aging.100431 · Cited by 192
“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
Rambold, A. S., & Lippincott‐Schwartz, J. (2011) · Cell Cycle · doi:10.4161/cc.10.23.18384 · Cited by 200
Zhang, M., Zhu, X., Zhang, Y., Cai, Y., Chen, J., Sivaprakasam, S., Gurav, A., Pi, W., Makala, L., Wu, J., et al. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.51 · Cited by 186
Inflammasome-Independent Modulation of Cytokine Response by Autophagy in Human Cells
Crișan, T. O., Plantinga, T. S., van de Veerdonk, F. L., Farcas, M. F., Stoffels, M., Kullberg, B. J., van der Meer, J. W. M., Joosten, L. A. B., & Netea, M. G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018666 · Cited by 193
“es [12,13].”
Willinger, T., & Flavell, R. A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1205305109 · Cited by 183
Autophagy for tissue homeostasis and neuroprotection
Mariño, G., Madeo, F., & Kroemer, G. (2011) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.10.001 · Cited by 195
“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
Fimia, G. M., & Piacentini, M. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0284-z · Cited by 185
“to undergo efficient proliferation after TCR stimulation [50].”
Background
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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