Premature T cell aging in major depression: A double hit by the state of disease and cytomegalovirus infection

Maria S Simon; Magdalini Ioannou; Gara Arteaga-Henríquez; Annemarie Wijkhuijs; Raf Berghmans; Richard Musil; Norbert Müller; Hemmo A Drexhage

doi:10.1016/j.bbih.2023.100608

Premature T cell aging in major depression: A double hit by the state of disease and cytomegalovirus infection

Brain Behav Immun Health. 2023 Feb 27:29:100608. doi: 10.1016/j.bbih.2023.100608. eCollection 2023 May.

Authors

Maria S Simon¹, Magdalini Ioannou², Gara Arteaga-Henríquez^{3

4}, Annemarie Wijkhuijs⁵, Raf Berghmans⁶, Richard Musil¹, Norbert Müller¹, Hemmo A Drexhage⁵

Affiliations

¹ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University, 80336, Munich, Germany.
² Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, 9713, GZ, Netherlands.
³ Department of Psychiatry, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
⁴ Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain.
⁵ Department of Immunology, Erasmus Medical Center, Rotterdam, 3015, GD, Netherlands.
⁶ Advanced Practical Diagnostics BVBA, Turnhout, 2300, Belgium.

Abstract

Introduction: Previous research indicates that premature T cell senescence is a characteristic of major depressive disorder (MDD). However, known senescence inducing factors like cytomegalovirus (CMV) infection or, probably, childhood adversity (CA) have not been taken into consideration so far.

Objective: Differentiation and senescent characteristics of T cells of MDD patients were investigated in relation to healthy controls (HC), taking the CMV seropositivity and CA into account.

Methods: 127 MDD and 113 HC of the EU-MOODSTRATIFICATION cohort were analyzed. Fluorescence activated cell sorting (FACS) analysis was performed to determine B, NK, and T cell frequencies. In a second FACS analysis, naïve, effector memory (Tem), central memory (Tcm), effector memory cells re-expressing RA (TEMRA), as well as CD28⁺ and CD27⁺ memory populations, were determined of the CD4⁺ and CD8⁺ T cell populations in a subsample (N = 35 MDD and N = 36 HC). CMV-antibody state was measured by IgG ELISA and CA by the Childhood Trauma Questionnaire.

Results: We detected a CMV-antibody positivity in 40% of MDD patients (35% HC, n. s.) with seropositive MDD cases showing a higher total childhood trauma score. Second, a higher inflation of memory CD4⁺ T helper cells in CMV seronegative patients as compared to seronegative HC and reduced numbers of naïve CD4⁺ T helper cells in CMV seropositive patients (not in CMV seropositive HC) were found. Third, a higher inflation of memory CD8⁺ T cytotoxic cells in CMV seropositive cases as compared to CMV seropositive HC, particularly of the TEMRA cells, became apparent. Higher percentages of CD4⁺ TEMRA and late stage CD27^-CD28^- TEMRA cells were similar in both HC and MDD with CMV seropositivity. Overall, apportioning of T cell subpopulations did not differ between CA positive vs negative cases.

Conclusions: MDD patients show several signs of a CMV independent "MDD specific" premature T cell aging, such as a CMV independent increase in CD4⁺ T memory cells and a latent naïve CD4 T-cell reduction and a latent CD8⁺ T-cell increase. However, these two latent T cell senescence abnormalities only become evident with CMV infection (double hit).

Keywords: CMV; Childhood trauma; Major depressive disorder; Senescence; T cytotoxic cell; T helper cell.