IL-10 producing regulatory type 1 (Tr1) T cells are instrumental in the regulation of autoimmunity and graft versus host disease. However, the molecular mechanisms controlling their differentiation are largely unknown. During the course of our studies to investigate the signaling pathways involved in the differentiation of Tr1 cells we obtained preliminary data which demonstrate that the Aryl Hydrocarbon Receptor (AHR) plays an important role during the differentiation of Tr1 cells. We found that AHR expression is induced in T cells by Tr1- promoting conditions, and controls the synthesis of IL-10 and the autocrine Tr1 growth factor IL-21. Moreover, we found that in Tr1 cells, AHR interacts with c-Maf, a transcription factor known to control il10 expression in T cells. In vivo, mice carrying a mutant AHR receptor show and impaired generation of Tr1 cells. We also found that AHR activation in dendritic cells (DC) triggers the differentiation of tolerogenic DC that produce IL-10, IL- 27 and TGF21, support Tr1 differentiation and suppress the development of experimental autoimmune encephalomylelitis (EAE). All in all, these data suggest that AHR signaling on T cells and DC plays an important role during the differentiation of Tr1 cells. We hypothesize that AHR controls the differentiation of Tr1 cells which play a crucial role in the control of inflammation. To address our hypothesis we will investigate the following Specific Aims:
SPECIFIC AIM 1. How does AHR signaling in T cells promote the differentiation of Tr1 cells? We will study the interaction of AHR with STAT proteins and the cooperation of c-Maf and AHR during the control of the expression of il10 and the autocrine growth factor il21.
SPECIFIC AIM 2. How does AHR signaling in DC promote the differentiation of Tr1 cells? In this aim we will study the induction of tolerogenic DC by AHR activation, DC that promote the differentiation of Tr1 cells at the expense of a decreased ability to polarize Th1 and Th17 cells.
SPECIFIC AIM 3. Does AHR signaling control the induction of functional Tr1 cells in vivo? In this Aim, we will study how effector and regulatory T cells and DC interact in vivo to control experimental autoimmune encephalomyelitis (EAE). Relevance to public health: Therapies aimed at the induction and expansion of Tr1 cells are likely to be beneficial for the treatment of human autoimmune disorders, but the signaling pathways that control the differentiation of Tr1 cells are still largely unknown. Based on our findings on AHR signaling in the control of Tr1 cell differentiation, targeting of AHR provides a new avenue to manipulate the immune response in autoimmune diseases.

Public Health Relevance

Autoimmune diseases such as multiple sclerosis, type 1 diabetes and rheumatoid arthritis are caused by the uncontrolled activity of the immune system. We will investigate how a protein called Aryl Hydrocarbon Receptor controls the immune system and how affecting it ameliorates an animal model of multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093903-04
Application #
8610231
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Lapham, Cheryl K
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$380,430
Indirect Cost
$155,430
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Rothhammer, Veit; Quintana, Francisco J (2016) Environmental control of autoimmune inflammation in the central nervous system. Curr Opin Immunol 43:46-53
Covacu, Ruxandra; Philip, Hagit; Jaronen, Merja et al. (2016) System-wide Analysis of the T Cell Response. Cell Rep 14:2733-44
Goettel, Jeremy A; Gandhi, Roopali; Kenison, Jessica E et al. (2016) AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice. Cell Rep 17:1318-1329
Rothhammer, Veit; Mascanfroni, Ivan D; Bunse, Lukas et al. (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22:586-97
Caballero-Hernandez, Diana; Toscano, Miguel G; Cejudo-Guillen, Marta et al. (2016) The 'Omics' of Amyotrophic Lateral Sclerosis. Trends Mol Med 22:53-67
Takenaka, Maisa C; Quintana, Francisco J (2016) Achieving Tolerance with Perforin-Secreting Dendritic Cells. Trends Mol Med 22:3-4
Rothhammer, Veit; Quintana, Francisco J (2015) Control of autoimmune CNS inflammation by astrocytes. Semin Immunopathol 37:625-38
Farez, Mauricio F; Mascanfroni, Ivan D; Méndez-Huergo, Santiago P et al. (2015) Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses. Cell 162:1338-52
Mascanfroni, Ivan D; Takenaka, Maisa C; Yeste, Ada et al. (2015) Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nat Med 21:638-46

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