IL-10 producing type 1 regulatory T cells (Tr1 cells) play an important role in controlling the immune response. Thus, Tr1 cells are potential targets for treating inflammatory disorders, but little is known about the control of their differentiation, stability and function. We have found that the transcription factor aryl hydrocarbon receptor (AHR) promotes Tr1 cell differentiation. AHR drives the expression of target genes in Tr1 cells, for example Entpd1 which codes for CD39. CD39 degrades extracellular adenosine triphosphate (eATP) and synthesizes immunosuppressive adenosine. We now found that: 1) eATP and hypoxia, which characterize inflamed tissues, inhibit Tr1 cell differentiation. 2) eATP and hypoxia activate the hypoxia- inducible factor-1? (HIF1?), which inhibits AHR-driven gene expression. 3) CD39 expressed in Tr1 cells (CD39Tr1) promotes Tr1 cell differentiation by depleting eATP. 4) CD39Tr1 deficiency impairs Tr1 cell differentiation and suppressive function. 5) CD39 expressed in DCs (CD39DC) promotes Tr1 cell differentiation. These findings suggest that CD39 controls Tr1 cell dependent immune regulation by stabilizing AHR-driven gene expression. We hypothesize that the balance between AHR/CD39 and eATP/HIF1? controls Tr1 cells. The objective of this project is to elucidate the role of these novel pathways on Tr1 cells, and their relevance for multiple sclerosis (MS) and other autoimmune diseases.
Our specific aims are:
Specific Aim 1 : What is the role of CD39Tr1 in Tr1 cell stability and function? CD39Tr1 deficiency impairs AHR-driven gene expression and suppressive function in Tr1 cells. These data suggest that by depleting eATP, CD39Tr1 stabilizes the AHR-driven transcriptional program of Tr1 cells. Thus, we propose to: 1) Define the role of CD39Tr1 on Tr1 cell stability during experimental autoimmune encephalomyelitis (EAE). 2) Determine the effects of eATP and hypoxia on Tr1 cell stability and their control by CD39Tr1. 3) Establish the effects of eATP and hypoxia on the transcriptional program of Tr1 cells.
Specific Aim 2 : Does CD39Tr1 control human Tr1 cells? The roles of AHR/CD39 and eATP/HIF1? on human Tr1 cells and their therapeutic potential are unknown. Thus, we propose to: 1) Establish the roles of AHR/CD39 and eATP-Hypoxia/HIF1? on the differentiation of human Tr1 cells. 2) Determine whether deficits in CD39+ Tr1 cells are associated to MS.
Specific Aim 3 : How does CD39DC control Tr1 cells? CD39DC promotes IL-10 expression by T cells in vitro and limits autoimmune inflammation. Thus, we propose to: 1) Determine the role of CD39DC in controlling Tr1 cells in vivo. 2) Establish the role of eATP signaling in T cells on the control of Tr1 cells by CD39DC. 3) Define the effects of CD39DC on DC phenotype and function. IN SUMMARY, we use unique tools in mouse and human systems to study novel pathways that control Tr1 cells, as well as potential therapeutic targets for MS and other autoimmune diseases. 2

Public Health Relevance

Autoimmune diseases like multiple sclerosis are caused by the uncontrolled activity of the immune system. This project proposes to use mouse and human systems to study novel molecular pathways that control the immune response and to identify potential targets for therapeutic immune modulation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Esch, Thomas R
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Brigham and Women's Hospital
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Gutiérrez-Vázquez, Cristina; Quintana, Francisco J (2018) Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity 48:19-33
Quintana, Francisco J (2018) Astrocytes play a crucial role in the formation and evolution of MS lesions-Commentary. Mult Scler :1352458518796693
Xie, Anyan; Robles, René J; Mukherjee, Samiran et al. (2018) HIF-1?-induced xenobiotic transporters promote Th17 responses in Crohn's disease. J Autoimmun 94:122-133
Rothhammer, Veit; Borucki, Davis M; Kenison, Jessica E et al. (2018) Detection of aryl hydrocarbon receptor agonists in human samples. Sci Rep 8:4970
Wheeler, Michael A; Rothhammer, Veit; Quintana, Francisco J (2017) Control of immune-mediated pathology via the aryl hydrocarbon receptor. J Biol Chem 292:12383-12389
Nirschl, Christopher J; Suárez-Fariñas, Mayte; Izar, Benjamin et al. (2017) IFN?-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment. Cell 170:127-141.e15
Gabriely, Galina; Wheeler, Michael A; Takenaka, Maisa C et al. (2017) Role of AHR and HIF-1? in Glioblastoma Metabolism. Trends Endocrinol Metab 28:428-436
Quintana, Francisco J (2017) Astrocytes to the rescue! Glia limitans astrocytic endfeet control CNS inflammation. J Clin Invest 127:2897-2899
Rothhammer, Veit; Kenison, Jessica E; Tjon, Emily et al. (2017) Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci U S A 114:2012-2017
Quintana, Francisco J; Prinz, Marco (2017) A gut feeling about multiple sclerosis. Proc Natl Acad Sci U S A 114:10528-10529

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