Each tissue of the body constitutes a unique environment made up of specialized resident cell types (e.g., neurons in brain). However, immune cells such as CD4+ T lymphocytes circulate throughout the body, and need to coordinate protective immune responses in diverse tissues. Thus, CD4+ T cells are thought to acquire tissue-specific functions to survive and function in these diverse environments. Few tissues are as unique as the intestine, which is both comprised of many differentiated cells types, and exposed to numerous byproducts (i.e., metabolites) associated with digestion, nutrient uptake, and gut bacteria. It has been widely speculated that T cells acquire adaptive functions in the intestine, although specific mechanisms have not been described. We have discovered that intestinal CD4+ T cells express high levels of the multidrug transporter MDR1 in patients with inflammatory bowel disease (IBD) and in mouse models of IBD. MDR1 is a member of a large family of membrane-associated drug pumps known as ATP-binding cassette (ABC) transporters. Although MDR1 has been studied for 30 years based on regulation of drug responses in healthy tissues and malignant tumors, little is known about its normal physiologic functions. We have found that MDR1 interacts with naturally occurring intestinal metabolites, known as bile acids, and that loss of Mdr1 in mouse CD4+ T cells disrupts intestinal homeostasis and provokes severe inflammatory disease. This proposal will define mechanisms by which Mdr1 expression, and thus intestinal T cell adaptation, is regulated. We hypothesize that Mdr1 expression is induced in CD4+ T cells upon entering the gut by resident dendritic cells (DCs). Indeed, our data show that intestinal DCs have a unique capacity to induce Mdr1 expression in cultured nave CD4+ T cells, and that at least part of this activity is due to production of a soluble factor that can be collected and transferred in culture supernatant.
In Aim 1, we will use biochemical methods to fractionate and identify the active DC- derived component(s) that induce Mdr1 in CD4+ T cells. In addition, little is known about how MDR1 expression is controlled at the level of transcription. Thus, we will define the transcription factrs that direct Mdr1 expression in intestinal CD4+ T cells. We hypothesize that nuclear receptors (NRs), which are implicated in regulating MDR1 transcription in non-immune cell types, direct the transcription of MDR1 in T cells. We will test this hypothesis in Aim 2, using an unbiased screening approach that combines shRNA-mediated knockdown of the 49 mouse NRs, advanced DNA sequencing technology, and our established T cell transfer mouse model of IBD, to identify the NR(s) that orchestrate Mdr1 expression in CD4+ T cells in vivo. These experiments will define novel mechanisms by which CD4+ T cells adapt to the hostile environment of the intestine, and will resolve how signals from DCs induce Mdr1 expression in CD4+ T cells. These studies have broad implications in understanding specialized, tissue-specific T cell functions, and have particular relevance to IBD.
CD4+ T lymphocytes acquire unique functions in different tissues to coordinate immune responses throughout the body. We have found that the multidrug transporter MDR1 is specifically induced in intestinal CD4+ T cells, where it interacts with toxic metabolites in the gut and safeguards against severe intestinal inflammation. Our research team will identify the environmental cues and signaling pathways that control MDR1 expression in intestinal CD4+ T cells, thus enabling their adaptation to the intestinal milieu.
|Cao, Wei; Kayama, Hisako; Chen, Mei Lan et al. (2017) The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids. Immunity 47:1182-1196.e10|
|Chen, Mei Lan; Sundrud, Mark S (2016) Cytokine Networks and T-Cell Subsets in Inflammatory Bowel Diseases. Inflamm Bowel Dis 22:1157-67|