Elsevier

Brain, Behavior, and Immunity

Volume 87, July 2020, Pages 795-803
Brain, Behavior, and Immunity

Diagnosis-independent loss of T-cell costimulatory molecules in individuals with cytomegalovirus infection

https://doi.org/10.1016/j.bbi.2020.03.013Get rights and content

Highlights

  • CMV seropositivity was associated with immunosenescence-related T-cell phenotypes.

  • Diagnosis of MDD did not affect T-cell profiles, nor did it interact with CMV status.

  • MDD females were more likely to be CMV positive, whereas MDD males were less likely to be CMV positive compared with sex-matched controls.

Abstract

Major depressive disorder (MDD) is associated with physiological changes commonly observed with increasing age, such as inflammation and impaired immune function. Age-related impaired adaptive immunity is characterized by the loss of naive T-cells and the reciprocal accumulation of memory T-cells together with the loss of T-cell co-stimulatory molecules. Additionally, the presence and activity of cytomegalovirus (CMV) alters the architecture of the T-cell compartment in a manner consistent with premature aging. Because CMV is also thought to reactivate with psychological stress, this study tested whether MDD influences age-related phenotypes of T-cell populations in the context of CMV infection in young and middle-aged adults. Morning blood samples from volunteers with a DSM-IV diagnosis of MDD (n = 98, mean age(SD) = 36(10) years, 74.5% female, 57.1% CMV+) and comparison controls (n = 98, mean age(SD) = 34(10) years, 68.4% female, 51.0% CMV+) were evaluated for CMV IgG antibody status and the distribution of late differentiated (CD27CD28) cells within CD4+ and CD8+ T-cell subsets, i.e. naive (CCR7+CD45RA+), effector memory (EM, CCR7CD45RA), central memory (CM, CCR7+CD45RA) and effector memory cells re-expressing CD45RA (EMRA, CCR7CD45RA+). Mixed linear regression models controlling for age, sex, ethnicity and flow cytometry batch showed that CMV seropositivity was associated with a reduction in naive T-cells, expansion of EMRA T-cells, and a greater percent distribution of CD27CD28 cells within CD4+ and CD8+ memory T-cell subsets (p’s < 0.004), but there was no significant effect of MDD, nor any significant interaction between CMV and diagnosis. Unexpectedly, depressed men were less likely to be CMV+ and depressed women were more likely to be CMV+ than sex-matched controls suggesting a possible interaction between sex and MDD on CMV susceptibility, but this three-way interaction did not significantly affect the T-cell subtypes. Our findings suggest that depression in young and middle-aged adults does not prematurely advance aging of the T-cell compartment independently of CMV, but there may be significant sex-specific effects on adaptive immunity that warrant further investigation.

Section snippets

Background

Lymphoproliferative response to mitogen, natural killer cell cytotoxicity, and virus-specific T-cell response are suppressed in a subset of depressed patients (Irwin and Miller, 2007, Zorrilla et al., 2001). Relevant to these findings is the link between depression and poor control of chronic viral infections (Evans et al., 2002, Phillips et al., 2008) and attenuated response to immunization or accelerated loss of vaccine-induced immunogenicity over time (Afsar et al., 2009, Ford et al., 2019b,

Study participants

The study was approved by the Western Institutional Review Board and was conducted according to the principles expressed in the Declaration of Helsinki. Volunteers gave written consent to participate in a study involving neuroimaging and immunophenotyping. One hundred participants with a diagnosis of MDD and 100 comparison controls with no personal history of a psychiatric disorder were included in this sub-study. The groups were matched for age and sex. Diagnoses were determined according to

Results

Of the 200 samples initially selected for analysis, three samples were excluded because of non-specific binding of the CD45RA-PE-Cy7 antibody and one was excluded due to lack of remaining plasma for CMV antibody testing. Within the MDD group there was no difference between CMV+ and CMV subjects in MADRS scores or in recent history of psychotropic medication use other than sleep aids (p’s > 0.10). ETI-SR and CTQ scores were higher in MDD compared to controls (p’s < 0.001) and in CMV+ compared

Discussion

This investigation tested the hypothesis that there is an interaction between CMV and depression such that young and middle-aged adults with MDD who are also CMV+ would have greater premature accumulation of age-related T-cell phenotypes than non-depressed CMV+ controls. There were two main results. The principal finding was that no such interaction was evident. Although CMV infection was associated with an age-related T-cell phenotype, this relationship was independent of MDD diagnosis.

Acknowledgments

The authors thank all the research participants and wish to acknowledge the contributions of Brenda Davis, Debbie Neal, Chibing Tan, and Ashlee Rempel from the laboratory of TKT at the University of Oklahoma Integrative Immunology Center towards the transport, processing, and handling of all blood samples.

Funding

This work has been supported in part by The William K. Warren Foundation, National Institute of Mental Health Award Number R21MH113871, and the National Institute of General Medical Sciences Center Grant Award Number 1P20GM121312. RY has received support from the Stanley Medical Research Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financial disclosures

Dr. Paulus has received royalties for an article about methamphetamine use disorder from UpToDate. The other authors have no disclosures.

Ethics Statement

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.

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