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LB1264 - Endocrine disrupting chemicals affect T cell phenotypes and show a role for environmental factors in MS pathophysiology. (ID 2162)
Autoimmune diseases, including Multiple Sclerosis (MS), are more common in females, suggesting that immune-endocrine mechanisms are central for polarizing the immune response and maintaining tolerance. The accelerated use of chemicals in consumer products has called attention to a subset of additives used during manufacturing of goods and materials, termed endocrine disrupting chemicals (EDCs). These synthetic compounds are structural mimics of endogenous hormones and may therefore drive immune cells to enhanced or different outcomes. In recent decades, the increased application of EDCs across daily-use products has been coincident with an increase in the female to male MS susceptibility ratio. Involvement of T cells in MS is an active area of research, but the potential role of environmental factors in T cell differentiation has not been fully resolved and could inform on the sex-bias of MS disease.
Our study thus sought to determine whether EDCs adversely modulate T cell phenotypes and to identify which immune populations are most at-risk for deregulation by environmental factors.
Peripheral blood mononuclear cells (PBMCs) were isolated from female healthy controls (HC) and MS patients and in vitro exposure to EDCs, bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP), was maintained throughout T cell conditioned differentiation. Negative selection was carried out on remaining PBMCs to isolate CD4 T cells for additional regulatory T cell (Treg) differentiation. Exposure to EDCs was similarly maintained throughout Treg differentiation. On a set-endpoint, cells were harvested and analyzed by flow cytometry using a Treg or multi-parameter T cell panel. Dimensionality reduction clustering and high parameter discovery using t-distributed stochastic neighbor embedding were used to identify EDC induced changes in T cell phenotypes. Data was collected across two batches (n=8 per group) and validated across one batch (n=3 per group). Final results (n=16) will include batch effect normalization.
EDCs altered the phenotype and activation state of T cells, particularly BPA and low dose DEHP (10 nM) which led to increased central memory T cells (TCM). The TCM population was also more activated across EDC treatments, relative to untreated controls. These observations held true of both CD4 and CD8 T cells. For Treg differentiation, we identified only modest effects for BPA only, on total Tregs (Foxp3+CD25+); EDC treatments had no effect on Treg expression of latency-associated peptide (LAP).
Phenotyping of EDC-regulated T cells helps to elucidate population subtypes that could pose a risk for MS progression and severity. Results also emphasize the role of environmental factors in MS pathophysiology and offer an explanation for the sex-bias of MS disease.