The role of CD4+ T cell differentiation in cytomegalovirus-associated parahippocampal volume reduction and depressive symptoms: a dual-sample study.

Cytomegalovirus (CMV) establishes lifelong infection and promotes an immunosenescent T cell profile characterized by depletion of naïve cells and expansion of terminally differentiated effector memory cells re-expressing CD45RA (TEMRA). We examined whether CMV-related T cell differentiation was associated with brain structure and depressive symptoms in two complementary cohorts. In a neuroimaging cohort of 129 adults, higher CD4+ TEMRA percentages was associated with lower parahippocampal volume (β = -0.27, 95% CI [-0.42, -0.11], pFDR = 0.022). However, no T cell measure significantly mediated the association between CMV serostatus and parahippocampal volume after FDR correction. In a population-based sample of 5,759 older adults from the Health and Retirement Study, higher CD4+ TEMRA:naïve ratios, reflecting relative expansion of TEMRA cells and depletion of naïve CD4+ T cells, were associated with greater depressive symptom severity across three assessments from 2016 to 2020 (β = 0.097, 95% CI [0.074, 0.119], pFDR < 0.001). Structural equation models indicated significant indirect associations between CMV seropositivity and depressive symptoms through the CD4+ TEMRA:naïve ratio and CD4+ naïve cells. These findings link CMV-related T cell differentiation to reduced parahippocampal volume and increased depressive symptoms. Larger longitudinal studies integrating immunophenotyping, neuroimaging, and clinical outcomes in the same participants are needed to test this proposed pathway.