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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]
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“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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The inducible role of autophagy in cell death: emerging evidence and future perspectives
Huang, X., Yan, H., Xu, Z., Yang, B., Luo, P., & He, Q. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02135-w · Cited by 64
“Finally, autophagy is required for the survival and proliferation of T lymphocytes [171], and inhibition of autophagy in hepatocytes causes the accumulation of lipid droplets, which ultimately leads to the depletion of CD4 + T cells [164, 172].”
Alessandri, C., Ciccia, F., Priori, R., Astorri, E., Guggino, G., Alessandro, R., Rizzo, A. G., Conti, F., Minniti, A., Barbati, C., et al. (2017) · Arthritis Research & Therapy · doi:10.1186/s13075-017-1385-y · Cited by 55
“T lymphocytes displayed increased cell death, and atg5/ CD4 and CD8 T cells demonstrated deficient proliferation after T cell receptor stimulation [15]; atg7-deficient T lymphocytes had increased cell death and also showed expanded mitochondria, expanded ER content, and altered calcium flux [33].”
BackgroundYang, X. (2007) · Frontiers in bioscience · doi:10.2741/2775 · Cited by 55
“A recent report showed that in the autophagy gene Atg5 deficient mice, CD4+ and CD8+ T cells fail to undergo efficient proliferation after TCR stimulation, suggesting a critical role for Atg5 in T cell proliferation and survival (265).”
BackgroundAutophagy in Multiple Sclerosis: Two Sides of the Same Coin
Misrielal, C., Mauthe, M., Reggiori, F., & Eggen, B. J. L. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.603710 · Cited by 56
“…either Atg5- or Atg7-deficient CD4+ and CD8+ T-cells showed indeed multiple defects, including reduced survival and a defect in T-cell proliferation in response to antigen stimulation (Pua et al., 2007; Alirezaei et al., 2009; Keller and Lünemann, 2017; Paunovic et al., 2018; Yin et al., 2018).”
BackgroundMitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis
Cho, J., Seo, J.-W., Lim, C. H., Yang, L., Shiratsuchi, T., Lee, M., Chowdhury, R. R., Kasahara, H., Kim, J.-S., Oh, S. P., et al. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2014.230 · Cited by 56
“Antibodies used in the study were against: Ter119 (11-5921), CD71 (17-0711), B220 (11-0452, 48-0452), CD43 (12-0439), IgM (17-5790), IgD (11-5993), CD4 (17-0041), and CD8 (11-0081) (eBioscience, San Diego, CA, USA); c-Kit (553355) and Sca1 (557405) (BD Pharmingen, San Jose, CA, USA).”
Bata, N., & Cosford, N. D. P. (2021) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.1c00130 · Cited by 60
Macroautophagy, endogenous MHC II loading and T cell selection: the benefits of breaking the rules
Nedjic, J., Aichinger, M., Mizushima, N., & Klein, L. (2009) · Current Opinion in Immunology · doi:10.1016/j.coi.2009.01.013 · Cited by 56
Self-citationMocholí, E., Dowling, S. D., Botbol, Y. M., Gruber, R. C., Ray, A. K., Vastert, S. J., Shafit‐Zagardo, B., Coffer, P. J., & Macián, F. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.065 · Cited by 52
Proteasome inhibition drastically but reversibly impairs murine lymphocyte development
Maseda, D., Meister, S., Neubert, K., i, M. H., & Voll, R. E. (2008) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402297 · Cited by 53
“These mechanisms may induce apoptosis in a thymocyte-autonomous manner by enhancing autophagy, which is a critical process of cell death especially in the thymus”
BackgroundArsov, I., Li, X., Matthews, G., Coradin, J. H., Hartmann, B., Simon, A. K., Sealfon, S. C., & Yue, Z. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.59 · Cited by 53
“Recent evidence suggests that a form of nonapoptotic cell death, termed autophagy, could play a significant role in lymphocyte homeostasis.(1,2) Autophagy is an”
BackgroundCell-Intrinsic Roles for Autophagy in Modulating CD4 T Cell Functions
Jacquin, É., & Apétoh, L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01023 · Cited by 51
“However, the normal levels of membrane TCR and activation markers CD69 and CD25 indicated that autophagy inhibition does not alter TCR-driven activation of CD4 T cells (18).”
BackgroundResultInfluentialInfluence of Atg5 Mutation in SLE Depends on Functional IL-10 Genotype
López, P., Alonso‐Perez, E., Rodríguez‐Carrio, J., & Suárez, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078756 · Cited by 52
van Loosdregt, J., Spreafico, R., Rossetti, M. M., Prakken, B. J., Lotz, M., & Albani, S. (2013) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2013.02.026 · Cited by 51
Autophagy: from basic science to clinical application
Limbergen, J. V., Stevens, C., Nimmo, E., Wilson, D., & Satsangi, J. (2009) · Mucosal Immunology · doi:10.1038/mi.2009.20 · Cited by 53
Pathophysiological Role of Autophagy: Lesson from Autophagy-Deficient Mouse Models
Ichimura, Y., & Komatsu, M. (2011) · EXPERIMENTAL ANIMALS · doi:10.1538/expanim.60.329 · Cited by 50
“species (ROS) production as well as an imbalance in pro- and antiapoptotic protein expression [84, 85, 101].”
BackgroundFeng, C. G., Zheng, L., Lenardo, M. J., & Sher, A. (2009) · Autophagy · doi:10.4161/auto.5.2.7445 · Cited by 50
miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg)
Lu, Y., Gao, J., Zhang, S., Gu, J., Lu, H., Xia, Y., Zhu, Q., Qian, X., Zhang, F., Zhang, C., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0298-2 · Cited by 52
Therapeutic Modulation of Autophagy in Leukaemia and Lymphoma
Djavaheri‐Mergny, M., Giuriato, S., Tschan, M. P., & Humbert, M. (2019) · Cells · doi:10.3390/cells8020103 · Cited by 52
“Experiments in chimeric mice generated by transplantation of Atg5 or Atg7 knockout foetal liver cells into lethally irradiated congenic host demonstrated that mice with impaired autophagy show normal T cell development but cannot fully reconstitute the lymphoid compartment due to a drastic increase in cell death in th…”
BackgroundCalcium Homeostasis in the Control of Mitophagy
Perrone, M., Patergnani, S., Mambro, T. D., Palumbo, L., Wieckowski, M. R., Giorgi, C., & Pinton, P. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0122 · Cited by 52
Autophagy in CD4+ T-cell immunity and tolerance
Lünemann, J. D., & Münz, C. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.113 · Cited by 51
Recent insights on the putative role of autophagy in autoimmune diseases
Gianchecchi, E., Delfino, D. V., & Fierabracci, A. (2013) · Autoimmunity Reviews · doi:10.1016/j.autrev.2013.10.007 · Cited by 50
Lymphocyte Autophagy in Homeostasis, Activation, and Inflammatory Diseases
Arbogast, F., & Gros, F. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01801 · Cited by 51
“Consequently, ROS are more abundantly produced and are responsible for thymocyte apoptosis, leading to a decrease in thymic and peripheral populations (39).”
BackgroundResultInfluentialChen, M., Hu, Y., Hou, Y., Li, M., Tan, L., Chen, M., Geng, W., Tao, B., Jiang, H., Luo, Z. Y., et al. (2021) · Chemical Engineering Journal · doi:10.1016/j.cej.2021.130982 · Cited by 49
Corrado, M., Samardžić, D., Giacomello, M., Rana, N., Pearce, E. L., & Scorrano, L. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00747-6 · Cited by 49
A novel and functional variant within the ATG5 gene promoter in sporadic Parkinson's disease
Chen, D., Zhu, C., Wang, X., Feng, X., Pang, S., Huang, W., Hawley, R. G., & Yan, B. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.01.044 · Cited by 48
How Bacteria-Induced Apoptosis of Intestinal Epithelial Cells Contributes to Mucosal Inflammation
Hausmann, M. (2010) · International Journal of Inflammation · doi:10.4061/2010/574568 · Cited by 48
“Mutations in genes affecting the formation of autophagosomes [66, 67] or mutations in genes affecting lysosomal clearance of autophagosomes [68] are associated with increased frequency of apoptosis (reviewed in [65]).”
BackgroundInvolvement of autophagy in NK cell development and function
López‐Soto, A., Pedro, J. M. B., Kroemer, G., Galluzzi, L., & Gonzalez, S. R. (2017) · Autophagy · doi:10.1080/15548627.2016.1274486 · Cited by 46
Autophagy During Vertebrate Development
Aburto, M. R., Hurlé, J. M., Varela‐Nieto, I., & Magariños, M. (2012) · Cells · doi:10.3390/cells1030428 · Cited by 46
“generated mouse chimeras by transferring fetal liver cells from Atg5 mice after irradiation [111].”
BackgroundTorres, A., Luke, J. D., Kullas, A. L., Kapilashrami, K., Botbol, Y. M., Koller, A. A., Tonge, P. J., Chen, E. I., Macián, F., & van der Velden, A. W. M. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.4a0615-252r · Cited by 47
“Consistent with published evidence [40, 41], naı̈ve T cells exhibited a basal level of LC3-II expression and turnover that increased considerably following TCR engagement (Fig.”
ResultIs Autophagy Involved in the Diverse Effects of Antidepressants?
Rein, T. (2019) · Cells · doi:10.3390/cells8010044 · Cited by 45
Kusama, Y., Sato, K., Kimura, N., Mitamura, J., Ohdaira, H., & Yoshida, K. (2009) · APOPTOSIS · doi:10.1007/s10495-009-0390-2 · Cited by 50
“Additionally, Atg5 has been shown to be required for T and B lymphocyte survival during development [46, 47].”
BackgroundLi, B., Wang, F., Schall, N., & Muller, S. (2018) · Journal of Autoimmunity · doi:10.1016/j.jaut.2018.02.005 · Cited by 43
Fang, Q., & Chen, H. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.591356 · Cited by 41
“Other studies indicate that autophagy promotes the apoptosis of T cells (43).”
BackgroundAutophagy appears during the development of the mouse lower first molar
Yang, J., Zhu, L., Yuan, G., Chen, Y., Zhang, L., Zhang, L., & Chen, Z. (2012) · Histochemistry and Cell Biology · doi:10.1007/s00418-012-1016-2 · Cited by 43
“reported that the proliferation of CD4 and CD8 T cells was impaired upon TCR stimulation when Atg5 was deficient (Pua et al. 2007).”
BackgroundCastellazzi, M., Patergnani, S., Donadio, M., Giorgi, C., Bonora, M., Fainardi, E., Casetta, I., Granieri, E., Pugliatti, M., & Pinton, P. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1526-0 · Cited by 44
Links between Autophagy, Innate Immunity, Inflammation and Crohn’s Disease
Deretic, V. P. (2009) · Digestive Diseases · doi:10.1159/000228557 · Cited by 42
When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen
Schlie, K., Spowart, J. E., Hughson, L. R. K., Townsend, K. N., & Lum, J. J. (2011) · International Journal of Cell Biology · doi:10.1155/2011/470597 · Cited by 45
“Support for this idea comes from the finding that T cell stimulation by phorbol myristate acetate (PMA) and Ionomycin, which bypasses T cell receptor signalling, results in almost normal proliferation rates of autophagyincompetent T cells [91].”
BackgroundComputational modeling of heterogeneity and function of CD4+ T cells
Carbo, A., Hontecillas, R., Andrew, T., Eden, K. B., Mei, Y., Hoops, S., & Bassaganya-Riera, J. (2014) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2014.00031 · Cited by 43
“Furthermore, autophagy has been found to be essential for T cell survival and proliferation (Pua et al., 2007).”
BackgroundNrf2 promotes progression of non-small cell lung cancer through activating autophagy
Wang, J., Liu, Z., Hu, T., Han, L., Yu, S., Yao, Y., Ruan, Z., Tian, T., Huang, T., Wang, M., et al. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1312224 · Cited by 40
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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