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Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior
Open accessAbstract
Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.
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“Moreover, peripheral CD4+ T cells have been reported as the major contributors to the occurrence of mental disorders [15, 16].”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [15]
Citations
Cites
Stress and the brain: from adaptation to disease
de Kloet, E. R., Joëls, M., & Holsboer, F. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1683 · Cited by 4,621
The molecular neurobiology of depression
Krishnan, V., & Nestler, E. J. (2008) · Nature · doi:10.1038/nature07455 · Cited by 2,889
The role of the amygdala in fear and anxiety
Davis, M. (1992) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.15.030192.002033 · Cited by 2,357
Stress-induced immune dysfunction: implications for health
Glaser, R., & Kiecolt-Glaser, J. K. (2005) · Nature Reviews Immunology · doi:10.1038/nri1571 · Cited by 2,190
Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies
Naidoo, J., Page, D. B., Li, B. T., Connell, L. C., Schindler, K., Lacouture, M. E., Postow, M. A., & Wolchok, J. D. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv383 · Cited by 1,505
Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming
Buck, M. D., O’Sullivan, D., Geltink, R. I. K., Curtis, J. D., Chang, C., Sanin, D. E., Qiu, J., Kretz, O., Braas, D., van der Windt, G. J. W., et al. (2016) · Cell · doi:10.1016/j.cell.2016.05.035 · Cited by 1,491
Mechanisms of stress in the brain
McEwen, B. S., Bowles, N. P., Gray, J. D., Hill, M. N., Hunter, R. G., Karatsoreos, I. N., & Nasca, C. (2015) · Nature Neuroscience · doi:10.1038/nn.4086 · Cited by 1,386
Stress, depression, the immune system, and cancer
Reiche, E. M. V., Nunes, S. O. V., & Morimoto, H. K. (2004) · The Lancet Oncology · doi:10.1016/s1470-2045(04)01597-9 · Cited by 1,364
Mitochondrial Dynamics and Metabolic Regulation
Wai, T., & Langer, T. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.12.001 · Cited by 1,354
Metabolic regulation of mitochondrial dynamics
Mishra, P., & Chan, D. C. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201511036 · Cited by 1,143
Psychological Stress and Cardiovascular Disease
Dimsdale, J. E. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.12.024 · Cited by 1,117
How stress influences the immune response
Padgett, D. A., & Glaser, R. (2003) · Trends in Immunology · doi:10.1016/s1471-4906(03)00173-x · Cited by 1,059
The anatomical and cellular basis of immune surveillance in the central nervous system
Ransohoff, R. M., & Engelhardt, B. (2012) · Nature reviews. Immunology · doi:10.1038/nri3265 · Cited by 1,029
Activation of the left amygdala to a cognitive representation of fear
Phelps, E. A., O'Connor, K. J., Gatenby, J. C., Gore, J. C., Grillon, C., & Davis, M. (2001) · Nature Neuroscience · doi:10.1038/86110 · Cited by 895
The movers and shapers in immune privilege of the CNS
Engelhardt, B., Vajkoczy, P., & Weller, R. O. (2017) · Nature Immunology · doi:10.1038/ni.3666 · Cited by 893
Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour
Filiano, A. J., Xu, Y., Tustison, N. J., Marsh, R. L., Baker, W., Smirnov, I., Overall, C. C., Gadani, S. P., Turner, S. D., Weng, Z., et al. (2016) · Nature · doi:10.1038/nature18626 · Cited by 697
Wohleb, E. S., Hanke, M. L., Corona, A. W., Powell, N. D., Stiner, L. M., Bailey, M. T., Nelson, R. J., Godbout, J. P., & Sheridan, J. F. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0450-11.2011 · Cited by 638
Amygdala Response to Fearful Faces in Anxious and Depressed Children
Thomas, K. M. (2001) · Archives of General Psychiatry · doi:10.1001/archpsyc.58.11.1057 · Cited by 582
Animal models of anxiety disorders and stress
Campos, A. C., Fogaça, M. V., de Aguiar, D. C., & Guimarães, F. S. (2013) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2013-1139 · Cited by 510
Wang, Y.-L., Han, Q.-Q., Gong, W.-Q., Pan, D.-H., Wang, L.-Z., Hu, W., Yang, M., Li, B., Yu, J., & Liu, Q. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1054-3 · Cited by 438
Self-citationMitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology
Zhan, M., Brooks, C. R., Liu, F., Sun, L., & Dong, Z. (2013) · Kidney International · doi:10.1038/ki.2012.441 · Cited by 401
Multifaceted interactions between adaptive immunity and the central nervous system
Kipnis, J. (2016) · Science · doi:10.1126/science.aag2638 · Cited by 376
McKim, D. B., Weber, M. D., Niraula, A., Sawicki, C. M., Liu, X., Jarrett, B. L., Ramirez-Chan, K., Wang, Y., Roeth, R. M., Sucaldito, A. D., et al. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.64 · Cited by 365
Self-citationVajkoczy, P., Laschinger, M., & Engelhardt, B. (2001) · Journal of Clinical Investigation · doi:10.1172/jci12440 · Cited by 357
Animal models of anxiety in mice
Bourin, M., Petit‐Demoulière, B., Dhonnchadha, B. Á. N., & Hascoët, M. (2007) · Fundamental and Clinical Pharmacology · doi:10.1111/j.1472-8206.2007.00526.x · Cited by 277
Contributions of the central extended amygdala to fear and anxiety
Shackman, A. J., & Fox, A. S. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.0982-16.2016 · Cited by 269
Langlais, D., Barreiro, L. B., & Gros, P. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20151764 · Cited by 266
Inflammatory T helper 17 cells promote depression-like behavior in mice
Beurel, E., Harrington, L. E., & Jope, R. S. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.09.021 · Cited by 254
One-Third-the-Sites Transition-State Inhibitors for Purine Nucleoside Phosphorylase
Miles, R. W., Tyler, P. C., Furneaux, R. H., Bagdassarian, C. K., & Schramm, V. L. (1998) · Biochemistry · doi:10.1021/bi980658d · Cited by 250
Animal models of anxiety disorders in rats and mice: some conceptual issues
Steimer, T. J. (2011) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2011.13.4/tsteimer · Cited by 242
IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors
Chourbaji, S., Urani, A., Inta, I., Sanchis-Segura, C., Brandwein, C., Zink, M., Schwaninger, M., & Gass, P. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.05.001 · Cited by 241
Purine Nucleoside Phosphorylase Deficiency
Markert, M. L. (2012) · SpringerReference · doi:10.1007/springerreference_109893 · Cited by 240
Chronic stress, metabolism, and metabolic syndrome
Tamashiro, K. L., Sakai, R. R., Shively, C. A., Karatsoreos, I. N., & Reagan, L. P. (2011) · Stress · doi:10.3109/10253890.2011.606341 · Cited by 234
Purine Nucleoside Phosphorylase Deficiency Associated with Selective Cellular Immunodeficiency
STOOP, J. W., ZEGERS, B. J. M., Hendrickx, G. F. M., van Heukelom, L. H. S., Staal, G. E. J., Bree, P. K. D., Wadman, S. K., & BALLIEUX, R. E. (1977) · New England Journal of Medicine · doi:10.1056/nejm197703242961203 · Cited by 197
Dhabhar, F. S. (2008) · Allergy Asthma and Clinical Immunology · doi:10.1186/1710-1492-4-1-2 · Cited by 190
Uhlik, M. T., Good, L., Xiao, G., Harhaj, E. W., Zandi, E., Karin, M., & Sun, S. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.33.21132 · Cited by 154
Mitochondrial dynamics controls anti-tumour innate immunity by regulating CHIP-IRF1 axis stability
Gao, Z., Li, Y., Wang, F., Huang, T., Fan, K.-Q., Zhang, Y., Zhong, J.-Y., Cao, Q., Tong, C., Jia, J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01919-0 · Cited by 149
Self-citationThe effect of stress on the defense systems.
Dragoș, D., & Tănăsescu, M. D. (2010) · PubMed Central · Cited by 147
Lymphocytes from Chronically Stressed Mice Confer Antidepressant-Like Effects to Naive Mice
Brachman, R. A., Lehmann, M. L., Maric, D., & Herkenham, M. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2278-14.2015 · Cited by 130
Engler, H., Brendt, P., Wischermann, J., Wegner, A., Rohling, R., Schoemberg, T., Meyer, U., Gold, R., Peters, J., Benson, S., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.264 · Cited by 127
Purine metabolism is dysregulated in patients with major depressive disorder
Ali-Sisto, T., Tolmunen, T., Toffol, E., Viinamäki, H. T., Mäntyselkä, P. T., Valkonen‐Korhonen, M., Honkalampi, K. M., Ruusunen, A. A., Velagapudi, V., & Lehto, S. M. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.04.017 · Cited by 117
Theien, B. E., Vanderlugt, C. L., Eagar, T. N., Nickerson‐Nutter, C. L., Nazareno, R., Kuchroo, V. K., & Miller, S. D. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11717 · Cited by 112
Mitochondrial Basis for Immune Deficiency
Arpaia, E., Benveniste, P. M., Cristofano, A. D., Gu, Y., Dalal, I., Kelly, S. J., Hershfield, M. S., Pandolfi, P. P., Roifman, C. M., & Cohen, A. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.12.2197 · Cited by 111
Vaccination as a Novel Approach for Treating Depressive Behavior
Lewitus, G. M., Wilf-Yarkoni, A., Ziv, Y., Shabat-Simon, M., Gersner, R., Zangen, A., & Schwartz, M. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.07.014 · Cited by 109
Rattazzi, L., Piras, G., Ono, M., Deacon, R. M. J., Pariante, C. M., & D’Acquisto, F. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.54 · Cited by 108
Dual role of ALCAM in neuroinflammation and blood–brain barrier homeostasis
Lécuyer, M., Saint‐Laurent, O., Bourbonnière, L., Larouche, S., Larochelle, C., Michel, L., Charabati, M., Abadier, M., Zandee, S., Jahromi, N. H., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1614336114 · Cited by 107
Miyajima, M., Zhang, B., Sugiura, Y., Sonomura, K., Guerrini, M. M., Tsutsui, Y., Maruya, M., Vogelzang, A., Chamoto, K., Honda, K., et al. (2017) · Nature Immunology · doi:10.1038/ni.3867 · Cited by 103
Schramm, V. L., Li, C. M., Tyler, P. C., Furneaux, R. H., Kicska, G., Xu, Y., Grubmeyer, C. T., & Girvin, M. E. (1999) · Nature Structural Biology · doi:10.1038/9367 · Cited by 100
CD6 as a potential target for treating multiple sclerosis
Li, Y., Singer, N. G., Whitbred, J., Bowen, M. A., Fox, D. A., & Lin, F. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1615253114 · Cited by 88
Self-citationLi, Z., Ma, L., Kulesskaya, N., Võikar, V., & Tian, L. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.02.008 · Cited by 81
Purine Nucleoside Phosphorylase Deficiency
Osborne, W. R. A., Chen, S.-H., Giblett, E. R., Biggar, W. D., Ammann, A. A., & Scott, C. R. (1977) · Journal of Clinical Investigation · doi:10.1172/jci108826 · Cited by 75
Neurobehavioral Changes Resulting from Recombinase Activation Gene 1 Deletion
Cushman, J. D., Lo, J., Huang, Z. L., Wasserfall, C. H., & Petitto, J. M. (2003) · Clinical and Vaccine Immunology · doi:10.1128/cdli.10.1.13-18.2003 · Cited by 51
(2017) · Fortschritte der Neurologie · Psychiatrie · doi:10.1055/s-0043-104029 · Cited by 50
Darashchonak, N., Koepsell, B., Bogdanova, N. V., & von Versen‐Höynck, F. (2014) · BMC Pregnancy and Childbirth · doi:10.1186/1471-2393-14-2 · Cited by 42
Loss of T cells influences sex differences in behavior and brain structure
Rilett, K. C., Friedel, M., Ellegood, J., MacKenzie, R. N., Lerch, J. P., & Foster, J. A. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.02.016 · Cited by 38
Immune status influences fear and anxiety responses in mice after acute stress exposure
Clark, S. M., Sand, J., Francis, T. C., Nagaraju, A., Michael, K. C., Keegan, A. D., Kusnecov, A. W., Gould, T. D., & Tonelli, L. H. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.02.001 · Cited by 33
Clark, S. M., Michael, K. C., Klaus, J., Mert, A., Romano-Verthelyi, A. M., Sand, J., & Tonelli, L. H. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.09.030 · Cited by 30
Adenosine mediates sedative action of various centrally active drugs
Phillis, J. W., & Wu, P. H. (1982) · Medical Hypotheses · doi:10.1016/0306-9877(82)90074-3 · Cited by 30
IL-1 Receptor-Antagonist (IL-1Ra) Knockout Mice Show Anxiety-like Behavior by Aging
Wakabayashi, C., Numakawa, T., Odaka, H., Ooshima, Y., Kiyama, Y., Manabe, T., Kunugi, H., & Iwakura, Y. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.05.019 · Cited by 14
Depression, Antidepressants, and Inflammatory Bowel Disease: Implications for Future Models of Care
Gracie, D. J., & Ford, A. C. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.04.027 · Cited by 4
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2 of the 62 references couldn’t be matched to a known paper.
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Mittelbrunn, M., & Kroemer, G. (2021) · Nature Immunology · doi:10.1038/s41590-021-00927-z · Cited by 702
Function and therapeutic value of astrocytes in neurological diseases
Lee, H.-G., Wheeler, M. A., & Quintana, F. J. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00390-x · Cited by 662
The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders
Knezevic, E., Nenic, K., Milanovic, V., & Knezevic, N. N. (2023) · Cells · doi:10.3390/cells12232726 · Cited by 564
“Peripheral CD4+ T cells appear to be major contributors to the occurrence of mental disorders [118,119] (see Table 1).”
BackgroundImmune cell regulation of glia during CNS injury and disease
Greenhalgh, A. D., David, S., & Bennett, F. C. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0263-9 · Cited by 411
Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition
Pasciuto, E., Burton, O. T., Roca, C. P., Lagou, V., Rajan, W. D., Theys, T., Mancuso, R., Tito, R. Y., Kouser, L., Callaerts-Vegh, Z., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.026 · Cited by 368
Metadata
- Authors
- Fan, K.-Q., Li, Y.-Y., Wang, H.-L., Mao, X.-T., Guo, J.-X., Wang, F., Huang, L.-J., Li, Y.-N., Ma, X.-Y., Gao, Z.-J., Chen, W., Qian, D.-D., Xue, W.-J., Cao, Q., Zhang, L., Shen, L., Zhang, L., Tong, C., Zhong, J.-Y., Lu, W., Lu, L., Ren, K.-M., Zhong, G., Wang, Y., Tang, M., Feng, X.-H., Chai, R.-J., & Jin, J.
- Affiliations
- Zhejiang University (CN)
- Sir Run Run Shaw Hospital (CN)
- East China Normal University (CN)
- Southeast University (CN)
- ShanghaiTech University (CN)
- Corresponding author
- Jin, Jin
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 179
- Issue
- 4
- Pages
- 864-879.e19
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2983084556
- Cited by
- 312
- References
- 62
- Citations by year
- 2026: 30 · 2025: 43 · 2024: 57 · 2023: 45 · 2022: 54 · 2021: 41 · 2020: 39 · 2019: 3
- FWCI
- 11.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Key R&D Program of China (2018YFA0800503, 2018YFD0500100)
- Excellent Young Scientist Fund of NSFC (31822017)
- Zhejiang Provincial Natural Science Foundation of China (LR19C080001)
- Strategic Priority Research Program of the Chinese Academy of Science (XDA16010302)
- National Natural Science Foundation of China (81572651, 81771675, 81622013, 81700913)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- stress-induced anxiety, CD4+ T cells, leukotriene B4, mitochondrial fission, purine metabolism, xanthine, adenosine A1 receptor, oligodendrocytes, amygdala, IRF1, depression, social behavior disorders, mood disorders, T cell dysfunction
- MeSH terms
- Amygdala, Animals, Anxiety, Behavior, Animal, Brain Diseases, Metabolic, Disease Models, Animal, Humans, Oligodendroglia, Stress, Psychological, CD4-Positive T-Lymphocytes, Xanthine, Mice, Single-Cell Analysis, Transcriptome, Mitochondrial Dynamics
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