Determination of the mechanisms by which 2,3,78-tetrachlorodibenzo-p-dioxin (TCDD) suppress immunity are important for several reasons. First, there is potential for chronic low dose TCDD exposure to produce immunotoxicity and render populations susceptible to disease. Second, TCDD can be used as a model ligand to understand aryl hydrocarbon receptor (AHR) signaling in lymphocytes. Finally, identification of AHR ligands that produce less systemic toxicity than TCDD might lead to useful therapeutics for autoimmune and inflammatory diseases. We have established that subchronic low dose TCDD produced suppression of effector T cell function and attenuation of disease in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We determined that TCDD not only suppressed T cell cytokine production but also induced regulatory T cells (Tregs). The goal of this research proposal is to determine the effect of TCDD on regulatory B cell populations in EAE and assess the contribution that TCDD-treated regulatory B cells make to TCDD-mediated alterations in T cell function. We will test the hypothesis that the mechanism by which TCDD suppresses EAE involves induction of regulatory cells, which control effector and regulatory T cell responses. Our first specific aim (SA) will be to characterize the effects of TCDD on regulatory B cell populations with a focus on regulatory B cells that can alter T cell function through cell-cell interactions. Our second SA is to determine the role that TCDD-treated B regulatory cells have on TH1, TH2 and TH17 effector T cells. Our third SA is to determine the role that TCDD-treated B regulatory cells have on Tregs. We expect that the results from these studies will establish that TCDD can induce regulatory B cell populations that contribute to either suppression of effector T cell responses or induction of Tregs. The studies will also provide a comparison of the ability of TCDD to induce regulatory B cells in mouse and human. Another critical aspect of this research proposal is that several undergraduate students will be involved over the 3-year period and receive training in hypothesis testing, experimental design, data analysis and interpretation, and effective dissemination of results in both oral and written form.
Understanding the mechanisms by which TCDD alters immunity is important because it can produce immune suppression. In addition, ligands that act similarly to TCDD could be developed as therapeutics for autoimmune disease. Given the recent findings that regulatory B cells play critical roles in autoimmune disease, it is important to understand how TCDD and its receptor, AHR, alter regulatory B cell function.
