206. Adaptive immune system changes related to stress and depression: clinical and preclinical insights

Abstract

Abstract Background A challenge for developing new major depressive disorder (MDD) treatments is understanding how non-heritable risk factors like stress alter biological processes. We previously used preclinical animal models to demonstrate chronic psychosocial stress reorganizes the peripheral and meningeal immune milieu and that these shifts are related to depressive-like behavioral change. This work highlighted a potentially critical role for dysregulated feedback to CD4+ T cells of the adaptive immune system in the progression of stress-related disorders. In independent clinical studies of MDD, we have shown that blood CD4+ T cell levels are predictive of MDD status. Moreover, genetic risk variants for MDD are enriched in epigenetic ‘hotspots’ used by CD4+ T cells. Collectively, this motivates our present investigation into how early life stress (ELS) impacts CD4+ T cell biology in the context of MDD. We specifically examine epigenetic ‘reprogramming’ associated with ELS severity given the strongly predicative and long-lasting risk for MDD incurred by exposure. Aims & Objectives The primary aim of this study is to determine if ELS severity is associated with DNA methylation changes in peripheral blood CD4+ T cells collected from people with MDD and non-depressed controls. Our primary objective is to ascertain viable targets for future translational and pharmacological studies to address an unmet need in treatment-resistant MDD. Method Participants were recruited in two separate case-control study cohorts, consented to fasting blood draw, and completed the Childhood Trauma Questionnaire (CTQ). Peripheral CD4+ T cells were isolated, bulk lysed, and frozen. DNA was isolated and epigenome-wide methylation was profiled using Illumina’s EPIC microarray. Our statistical analysis plan has been preregistered (https://osf.io/eydvh/). We used multiple linear regression to independently test for epigenome-wide associations with CTQ score with Bonferroni correction across tested probes, controlling for demographic and technical variables. We also explored associations at an exploratory p-value threshold of p<1x10-5. Results Our initial analysis revealed 14 individual methylation sites with significant associations to ELS severity, including one locus known to influence gene expression of DLX1. Replication of these findings in an independent cohort is ongoing. Discussion & Conclusions Our previous work in a preclinical animal model for depression suggested stress dysregulates the balance of CD4+ T cell subtypes. Preliminary data from the present study suggests this may occur via altered epigenetic regulation of DLX1. DLX1 is essential for GABAergic interneuron development in the forebrain, where its expression is reduced by prenatal stress. In the immune system, DLX1 acts as a transcription factor for AHR, which in turn regulates the balance of CD4+ T cell subtypes, e.g., Th1, Treg, Th17/22. Collectively, our data-driven approach uncovered an unexpected link to DLX1 and AHR expression in CD4+ T cells; given active research into AHR agonists for inflammatory bowel disease and cancer, this pathway may represent an important area for future psychopharmacological research in the context of stress-related disorders such as MDD. These data, as well as data from an ongoing replication cohort and estimation of T cell methylation in bulk blood samples from the Generation Scotland cohort, will be further discussed.