Experimental autoimmune encephalomyelitis (EAE) is an animal model that reproduces many of the clinical and pathological features of multiple sclerosis (MS). The development and the progression of EAE, like other autoimmune diseases, results from the pathogenicity of effector cells and the negative regulation imposed by regulatory T cells (Tregs). Since Tregs express the Fox-P3 transcription factor, we have generated a Foxp3- EGFP "knock-in" mouse strain in order to track CD4+ CD25+ Fox-P3+ Tregs by GFP-expression. The Fox-P3- EGFP reporter mice readily develop EAE following immunization with myelin oligodendrocyte glycoprotein (MOG). With the help of an I-Ab/MOG35-55 tetramer, we are able to track the development and effector functions of MOG specific effector and Fox-P3+ regulatory T cells. Of all the encephalitogenic effector T cells, in recent years IL-17 producing Th17 cells have gained a lot of attention and are implicated in mediating tissue inflammation including EAE. We have found that IL-6, an acute phase protein, not only suppresses the generation of Fox-P3+ Treg cells induced by TGF-?, but in turn induces Th17 effector T cells. Based on this observation, we hypothesize that there is a reciprocal relationship between pathogenic Th17 cells and protective Fox-P3+ Treg cells, and cytokines like IL-6 produced by the innate immune system dictate the balance between pathogenic/regulatory T cells and the development of autoimmunity. In addition to IL-6, we have now observed that IL-4 can also suppress induction of Fox-P3 and together with TGF-? can induce a unique population of T cells that produces IL-9 and IL-10. These IL-9/IL-10 producing Th9 cells are not regulatory T cells but effector T cells that induce colitis and peripheral neuritis upon adoptive transfer into immunodeficient mice, however, what is their role in the induction of EAE has not been evaluated. We propose to: 1) Test the role of IL-6 in promoting tissue inflammation and in regulating the balance between pathogenic Th17 and Treg cells;2) Study the role of Th9 cells in the induction and regulation of EAE;and 3) Study the role of IL-23, a cytokine that expands and stabilizes Th17 cells, in generating pathogenic effector T cells and induction of tissue inflammation in the CNS. For studying the role of IL-23 in EAE, we have generated a novel IL-23R.GFP "knock-in" mouse strain, which in a heterozygous state becomes a reporter for IL-23 receptor expression and in the homozygous state becomes a "knock-out" line. With the availability of reporter mouse strains for Fox-P3+ and IL-23R+ cells, we are in a unique position to study how inflammatory cytokines particularly IL-6 regulate the balance between pathogenic and regulatory T cells and promote tissue inflammation and EAE.

Public Health Relevance

This project deals with studying the effects of proinflammatory cytokines (IL-6 and IL-23) on regulating the balance between protective regulatory T cells (Fox-P3+ Treg) and pathogenic effector T cells, including Th17 cells and a novel T cell subset named Th9 cells, during an autoimmune disease of the central nervous system called Experimental Autoimmune Encephalomyelitis (EAE). Using "reporter" mice for effector and regulatory T cells and autoantigen specific tetramers, we will be able to study the balance and interplay between antigen- specific effector and regulatory T cells during the autoimmune reaction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030843-20
Application #
8247801
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
1992-07-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
20
Fiscal Year
2012
Total Cost
$353,090
Indirect Cost
$124,152
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Kishi, Yasuhiro; Kondo, Takaaki; Xiao, Sheng et al. (2016) Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity. J Exp Med 213:2489-2501
Lee, Youjin; Mitsdoerffer, Meike; Xiao, Sheng et al. (2015) IL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitis. J Clin Invest 125:4011-20
Wang, Chao; Yosef, Nir; Gaublomme, Jellert et al. (2015) CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity. Cell 163:1413-27
Wang, Chao; Collins, Mary; Kuchroo, Vijay K (2015) Effector T cell differentiation: are master regulators of effector T cells still the masters? Curr Opin Immunol 37:6-10
Zhu, Chen; Sakuishi, Kaori; Xiao, Sheng et al. (2015) An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction. Nat Commun 6:6072
Gaublomme, Jellert T; Yosef, Nir; Lee, Youjin et al. (2015) Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell 163:1400-12
Xiao, Sheng; Brooks, Craig R; Sobel, Raymond A et al. (2015) Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation. J Immunol 194:1602-8
Peters, Anneli; Fowler, Kevin D; Chalmin, Fanny et al. (2015) IL-27 Induces Th17 Differentiation in the Absence of STAT1 Signaling. J Immunol 195:4144-53
Vega-Carrascal, Isabel; Bergin, David A; McElvaney, Oliver J et al. (2014) Galectin-9 signaling through TIM-3 is involved in neutrophil-mediated Gram-negative bacterial killing: an effect abrogated within the cystic fibrosis lung. J Immunol 192:2418-31

Showing the most recent 10 out of 65 publications