This is a revised PPG application to build a better understanding of T cell mechanisms in autoimmunity that has stemmed from the discovery of critical regulators of both T effector and T regulatory cells. We have discovered that IL-27 and the transcription factor aryl hydrocarbon receptor (AhR) play central roles in immune responses in animals and humans and these pathways impinge on all aspects of immune function, both adaptive and innate and include Tregs, Th17 cells and dendritic cells. Little is known about these new pathways, which appear crucial in CNS inflammation and have direct relevance to diseases such as multiple sclerosis. The primary goal of this program project grant (PPG) is to identify molecular mechanisms of how IL-27 inhibits effector T cells and induces regulatory Tr1 cells with a focus on two transcription factors cMaf and AhR, both of which are induced by IL-27 in responding Tr1 cells. The investigation of the inter-relationship of cytokines and transcription factors in both animal models and MS patients will allow a better basic understanding of immune abnormalities in MS and allow both the development of more specific immunomodulatory therapy and a mechanistic understanding of current therapies being used to treat MS. IFN?, a widely used first line therapy in MS has been shown to act in part by the induction of IL-27, underscoring the importance of studying this pathway in CNS autoimmunity. This PPG brings together four investigators, each with unique strengths and expertise to investigate this new area. Project 1: (Kuchroo) """"""""Transcriptional regulation of effector and regulatory T cells in EAE;Project 2: (Littman) """"""""Transcriptional network analysis of Tr1 cells."""""""" Project 3: (Quintana) """"""""Role of AhR in the control of the innate immune response during the development of EAE."""""""" and Project 4: (Weiner) """"""""Role of IL-27 and AhR in the regulation of human effector and regulatory T cells in healthy subjects and MS patients."""""""" The revised PPG will establish a Multi-tiered Expression Analysis Core consisting of two components: Project 2 will undertake expression analysis using RNA-seq and ChlP-seq technologies and Core B will undertake multiplex expression analysis using the latest digital Nanostring technology to analyze the expression of transcripts in subsets and rare populations. The core will service all projects. An Administrative Core will coordinate the various administrative aspects of the PPG and a Scientific Advisory Board has been assembled to provide scientific oversight.

Public Health Relevance

Our investigations are designed to provide a better basic understanding of immune abnormalities in multiple sclerosis and allow both the development of more specific immunomodulatory therapy and a mechanistic understanding of current therapies being used to treat MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
1P01NS076410-01A1
Application #
8415329
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Utz, Ursula
Project Start
2012-12-01
Project End
2017-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$1,128,637
Indirect Cost
$347,417
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Aschenbrenner, Dominik; Foglierini, Mathilde; Jarrossay, David et al. (2018) An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells. Nat Immunol 19:1126-1136
Meyer Zu Horste, Gerd; Przybylski, Dariusz; Schramm, Markus A et al. (2018) Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1. Immunity 48:556-569.e7
Joller, Nicole; Kuchroo, Vijay K (2017) Tim-3, Lag-3, and TIGIT. Curr Top Microbiol Immunol 410:127-156
Karwacz, Katarzyna; Miraldi, Emily R; Pokrovskii, Maria et al. (2017) Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation. Nat Immunol 18:412-421
Hu, Dan; Notarbartolo, Samuele; Croonenborghs, Tom et al. (2017) Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis. Nat Commun 8:1600
Chihara, Norio; Madi, Asaf; Karwacz, Katarzyna et al. (2016) Differentiation and Characterization of Tr1 Cells. Curr Protoc Immunol 113:3.27.1-3.27.10
Anderson, Ana C; Joller, Nicole; Kuchroo, Vijay K (2016) Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 44:989-1004
Meyer Zu Horste, Gerd; Wu, Chuan; Wang, Chao et al. (2016) RBPJ Controls Development of Pathogenic Th17 Cells by Regulating IL-23 Receptor Expression. Cell Rep 16:392-404
Mayo, Lior; Cunha, Andre Pires Da; Madi, Asaf et al. (2016) IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation. Brain 139:1939-57
Gaublomme, Jellert T; Yosef, Nir; Lee, Youjin et al. (2015) Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell 163:1400-12

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