T Cell Activation and Deficits in T Regulatory Cells Are Associated with Major Depressive Disorder and Severity of Depression

Overview

Journal Sci Rep

Specialty Science

Date 2024 May 15

PMID 38750122

Authors

Muanpetch Rachayon

Ketsupar Jirakran

Pimpayao Sodsai

Atapol Sughondhabirom

Michael Maes

Affiliations

Soon will be listed here.

Abstract

Major depressive disorder (MDD) is associated with T cell activation, but no studies have examined the combined effects of T cell activation and deficits in T regulatory (Treg) cells on the severity of acute phase MDD. Using flow cytometry, we determined the percentage and median fluorescence intensity of CD69, CD71, CD40L, and HLADR-bearing CD3+, CD4+, and CD8+ cells, and cannabinoid type 1 receptor (CB1), CD152 and GARP (glycoprotein A repetitions predominant)-bearing CD25+ FoxP3 T regulatory (Treg) cells in 30 MDD patients and 20 healthy controls in unstimulated and stimulated (anti-CD3/CD28) conditions. Based on cytokine levels, we assessed M1 macrophage, T helper (Th)-1 cell, immune-inflammatory response system (IRS), T cell growth, and neurotoxicity immune profiles. We found that the immune profiles (including IRS and neurotoxicity) were significantly predicted by decreased numbers of CD152 or GARP-bearing CD25+ FoxP3 cells or CD152 and GARP expression in combination with increases in activated T cells (especially CD8+ CD40L+ percentage and expression). MDD patients showed significantly increased numbers of CD3+ CD71+, CD3+ CD40L+, CD4+ CD71+, CD4+ CD40L+, CD4+ HLADR+, and CD8+ HLADR+ T cells, increased CD3+ CD71+, CD4+ CD71+ and CD4+ HLADR+ expression, and lowered CD25+ FoxP3 expression and CD25+ FoxP+ CB1+ numbers as compared with controls. The Hamilton Depression Rating Scale score was strongly predicted (between 30 and 40% of its variance) by a lower number of CB1 or GARP-bearing Treg cells and one or more activated T cell subtypes (especially CD8+ CD40L+). In conclusion, increased T helper and cytotoxic cell activation along with decreased Treg homeostatic defenses are important parts of MDD that lead to enhanced immune responses and, as a result, neuroimmunotoxicity.

Citing Articles

Development of machine-learning-driven signatures for diagnosing and monitoring therapeutic response in major depressive disorder using integrated immune cell profiles and plasma cytokines.

He S, Zhao F, Sun G, Shi Y, Xu T, Zhang Y Theranostics. 2024; 14(18):7265-7280.

PMID: 39629120 PMC: 11610142. DOI: 10.7150/thno.102602.

In major dysmood disorder, physiosomatic, chronic fatigue and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity.

Maes M, Almulla A, Zhou B, Algon A, Sodsai P Sci Rep. 2024; 14(1):7344.

PMID: 38538641 PMC: 10973347. DOI: 10.1038/s41598-024-57350-1.

Lower Nerve Growth Factor Levels in Major Depression and Suicidal Behaviors: Effects of Adverse Childhood Experiences and Recurrence of Illness.

Maes M, Rachayon M, Jirakran K, Sodsai P, Sughondhabirom A Brain Sci. 2023; 13(7).

PMID: 37509019 PMC: 10377511. DOI: 10.3390/brainsci13071090.

References

Ruedl C, Bachmann M, Kopf M . The antigen dose determines T helper subset development by regulation of CD40 ligand. Eur J Immunol. 2000; 30(7):2056-64. DOI: 10.1002/1521-4141(200007)30:7<2056::AID-IMMU2056>3.0.CO;2-S. View

Diehl L, den Boer A, Schoenberger S, van der Voort E, Schumacher T, Melief C . CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med. 1999; 5(7):774-9. DOI: 10.1038/10495. View

Hall B . CD4+CD25+ T Regulatory Cells in Transplantation Tolerance: 25 Years On. Transplantation. 2016; 100(12):2533-2547. DOI: 10.1097/TP.0000000000001436. View

Kaplan B . The role of CB1 in immune modulation by cannabinoids. Pharmacol Ther. 2012; 137(3):365-74. DOI: 10.1016/j.pharmthera.2012.12.004. View

Berg V, Modak M, Brell J, Puck A, Kunig S, Jutz S . Iron Deprivation in Human T Cells Induces Nonproliferating Accessory Helper Cells. Immunohorizons. 2020; 4(4):165-177. DOI: 10.4049/immunohorizons.2000003. View

Ots H, Tracz J, Vinokuroff K, Musto A . CD40-CD40L in Neurological Disease. Int J Mol Sci. 2022; 23(8). PMC: 9031401. DOI: 10.3390/ijms23084115. View

Mohd Ashari N, Mohamed Sanusi S, Mohd Yasin M, Che Hussin C, Wong K, Shafei M . Major depressive disorder patients on antidepressant treatments display higher number of regulatory T cells. Malays J Pathol. 2019; 41(2):169-176. View

Workman C, Szymczak-Workman A, Collison L, Pillai M, Vignali D . The development and function of regulatory T cells. Cell Mol Life Sci. 2009; 66(16):2603-22. PMC: 2715449. DOI: 10.1007/s00018-009-0026-2. View

Almulla A, Al-Hakeim H, Maes M . Chronic fatigue and affective symptoms in acute and long COVID are attributable to immune-inflammatory pathways. Psychiatry Clin Neurosci. 2022; 77(2):125-126. PMC: 9877923. DOI: 10.1111/pcn.13514. View

10.

Wang K, Gu J, Ni X, Ding Z, Wang Q, Zhou H . CD25 signaling regulates the function and stability of peripheral Foxp3+ regulatory T cells derived from the spleen and lymph nodes of mice. Mol Immunol. 2016; 76:35-40. DOI: 10.1016/j.molimm.2016.06.007. View

11.

Debnath M, Berk M, Maes M . Translational evidence for the Inflammatory Response System (IRS)/Compensatory Immune Response System (CIRS) and neuroprogression theory of major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2021; 111:110343. DOI: 10.1016/j.pnpbp.2021.110343. View

12.

Kitz A, Singer E, Hafler D . Regulatory T Cells: From Discovery to Autoimmunity. Cold Spring Harb Perspect Med. 2018; 8(12). PMC: 6280708. DOI: 10.1101/cshperspect.a029041. View

13.

Cullen J, McQuilten H, Quinn K, Olshansky M, Russ B, Morey A . CD4 T help promotes influenza virus-specific CD8 T cell memory by limiting metabolic dysfunction. Proc Natl Acad Sci U S A. 2019; 116(10):4481-4488. PMC: 6410826. DOI: 10.1073/pnas.1808849116. View

14.

Jahangard L, Behzad M . Diminished functional properties of T regulatory cells in major depressive disorder: The influence of selective serotonin reuptake inhibitor. J Neuroimmunol. 2020; 344:577250. DOI: 10.1016/j.jneuroim.2020.577250. View

15.

Hridi S, Barbour M, Wilson C, Franssen A, Harte T, Bushell T . Increased Levels of IL-16 in the Central Nervous System during Neuroinflammation Are Associated with Infiltrating Immune Cells and Resident Glial Cells. Biology (Basel). 2021; 10(6). PMC: 8229350. DOI: 10.3390/biology10060472. View

16.

Maes M, Meltzer H, Bosmans E, Bergmans R, Vandoolaeghe E, Ranjan R . Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord. 1995; 34(4):301-9. DOI: 10.1016/0165-0327(95)00028-l. View

17.

Zimmerman M, Martinez J, Young D, Chelminski I, Dalrymple K . Severity classification on the Hamilton Depression Rating Scale. J Affect Disord. 2013; 150(2):384-8. DOI: 10.1016/j.jad.2013.04.028. View

18.

Machhi J, Kevadiya B, Muhammad I, Herskovitz J, Olson K, Mosley R . Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders. Mol Neurodegener. 2020; 15(1):32. PMC: 7275301. DOI: 10.1186/s13024-020-00375-7. View

19.

Maes M, Moraes J, Congio A, Bonifacio K, Barbosa D, Vargas H . Development of a Novel Staging Model for Affective Disorders Using Partial Least Squares Bootstrapping: Effects of Lipid-Associated Antioxidant Defenses and Neuro-Oxidative Stress. Mol Neurobiol. 2019; 56(9):6626-6644. DOI: 10.1007/s12035-019-1552-z. View

20.

Chang X, Ma M, Chen L, Song Z, Zhao Z, Shen W . Identification and Characterization of Elevated Expression of Transferrin and Its Receptor TfR1 in Mouse Models of Depression. Brain Sci. 2022; 12(10). PMC: 9599150. DOI: 10.3390/brainsci12101267. View