Breaking Tolerance: Trichloroethylene Provides Survival Signals to Autoreactive CD4s in the Liver

About This Grant

PROJECT SUMMARY The industrial solvent and widespread environmental contaminant, trichloroethylene (TCE) has been linked to autoimmune disease in humans. How TCE impairs tolerance (i.e., unresponsiveness) to self-antigens leading to autoimmunity has not been explored. Autoimmune diseases (ADs) are a class of disorders that affect many different organs and tissues. However, all autoimmune diseases share a feature in common which is the ability of potentially pathogenic autoreactive cells to evade deletion. During early life, peripheral CD4+ cells are primarily comprised of recent thymic emigrants (RTE) which home to the liver. The liver is known to efficiently retain and tolerize self-reactive CD4s to where they are functionally unresponsive to their antigen. Thus, the liver is the first checkpoint in the periphery to filter, retain, and enforce tolerance to autoreactive CD4+ RTEs. The liver is also the site of TCE metabolism. Our Aims are designed to test the hypothesis that TCE, through its metabolite TCAH, delivers costimulatory signals to liver CD4 RTEs via CD28, thereby overriding inhibitory CTLA-4 signaling. This disruption promotes the survival of self-reactive CD4 RTEs by impairing CTLA-4-dependent tolerance mechanisms contributing to the development of ADs. This research will significantly advance the fields of toxicology and autoimmunity, where the origins of environmentally induced AD remain poorly understood. Aim 1 will assess TCE’s effects on RTE migration patterns in real-time in transgenic mice. Aim 2 will investigate TCAH-mediated costimulatory signaling in CD4 RTEs in vitro. Successful completion of these studies will determine how TCE alters key tolerance pathways in the liver resulting in a greater proportion of self-reactive effector memory (EM) peripheral CD4s capable of promoting AD.