Understanding the Aryl Hydrocarbon Receptor(AhR)-mediated generation of the intraepithelial lymphocytes

Abstract

Mature T cells are divided into two distinct major subsets: CD4 helper T (Th) cells and CD8 cytotoxic T (Tc) cells. Th cells essentially regulate immune responses by mediating the activation and controlling the function of other immune cell types, whereas Tc cells predominantly perform cytotoxic actions to infected or cancerous cells for immune protection. Although the fate to become a Th or Tc lineage is pre-determined during the T cell development in thymus, recent studies have revealed that mature Th cells, when losing Th lineage-determining transcription factor ThPOK, could upregulate Tc lineage-determining transcription factor Runx3, express CD8 and gain cytotoxic function. The cytotoxic reprogramming of Th cells is particularly observed in a significant population of intraepithelial lymphocytes (IELs). These cells are also shown to suppress intestinal inflammation. With the emerging evidence highlighting a fundamental role of gut immune homoeostasis for human health, my lab aims to identify signals that regulate the generation and function of CD8aa+CD4+ IELs and CD8aa+ IELs, particularly those extracellular and intracellular signals with potentials to be targeted for immunomodulation and immunotherapies. My PhD project focused on aryl hydrocarbon receptor (AhR) as a physiological regulator for CD8aa+CD4+ IELs and CD8aa+ IELs. AhR is an intracellular sensor of aryl hydrocarbons, which are enriched in the mammalian mucosal environment. Our results showed that certain AhR ligands induce CD8 expression on both mouse and human CD4 T cells ex vivo. Correspondingly, AhR-deficient mice demonstrated a defective generation of CD8aa+CD4+ IELs and CD8aa+ IELs. we further characterised the role of TCF1 in the AhR mediated generation of CD8aa+CD4+ IELs and CD8aa+ IELs. TCF1 is a key regulator maintained ThPOK expression, while we found that AhR through a directly binding on the Tcf7 promoter, inhibited its transcript, consequently leading to the suppressed expression of TCF1 in IELs. My study will provide the first detailed mechanism for the AhR-mediated regulation CD8aa+CD4+ IELs and CD8aa+ IELs. Such mechanism may further explain a general regulatory function of AhR in the homeostasis of T cells in the mucosal environment. Therefore, this new knowledge will pave the way for rationale-based design of immune interventions to enhance healthy gut and treat diseases, such as inflammatory bowel disease. Show more