Proteolipid protein (PLP) is the major protein component of central nervous system (CNS) myelin and is now recognized as a major autoantigen involved in the development of experimental autoimmune encephalomyelitis (EAE), an experimental model for human multiple sclerosis (MS). Just as MS is known to occur in certain human populations at a higher frequency, it is also known that some strains of mice are susceptible (e.g. SJL) while others are resistant (e.g. B10.S), even though the mice are H-2 identical. PLP 139-151 (HSLGKWLGHPDKF) is the dominant antigen for the induction of EAE in SJL mice, and we have found that the number of PLP 139-151 reactive T cells in the naive SJL repertoire is very high (1:20,000). In spite of this the SJL mice do not develop spontaneous EAE. We believe this is because SJL mice possess two different repertoires, that both recognize PLP 139-151, but which differ in their fine specificity and function in that one is pathogenic and the other is protective. We have developed two T cell receptor (TcR) transgenic mice which are representative of each of these repertoires. The transgenic mice expressing a pathogenic TcR develop EAE, whereas the mice expressing a non-pathogenic TcR do not. We have also generated an IAS/PLP 139-151 tetramer which binds and stains pathogenic T cells in transgenic and non-transgenic SJL mice. In this grant we propose to study the role of the two repertoires in the induction and regulation of EAE. We propose to: 1) Study the selection, expansion, differentiation and interplay between the two PLP 139-151 specific T cell repertoires in susceptible and resistant mice. By using the tetramers we will determine a) how the PLP 139-151 specific T cells expand and differentiate and b) how the two PLP 139-151 specific repertoires function in the susceptible-SJL and resistant-B 10.S mice. 2) Determine the cellular basis for the difference in susceptibility to EAE in SJL and B1O.S mice. By using transgenic T cells from the SJL and B10.S mice that express pathogenic TcR we will a) study the role of T cells; b) the role of APCs and their critical molecules (like class II, B7 and IL- 12) in susceptibility/resistance to EAE. 3) Analyze the mechanism by which expression of the alternate T cell repertoire specific for PLP 139-151 induces protection against EAE. Using the TcR transgenic mice that express the alternate TcR repertoire to PLP 139-151, we will a) determine whether these transgenic mice will develop EAE either spontaneously, of following immunization with the PLP 139-151 or other cross-reactive ligands; b) cross the two transgenic mice expressing pathogenic and protective TcRs and analyze the dual TcR transgenic mice for the development of EAE The results will provide basic information on the mechanism by which PLP specific T cells induce autoimmunity of the CNS and how different repertoires balance each other and regulate development of autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS030843-13
Application #
6769434
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Utz, Ursula
Project Start
1992-07-01
Project End
2006-03-31
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
13
Fiscal Year
2004
Total Cost
$367,650
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Gaublomme, Jellert T; Yosef, Nir; Lee, Youjin et al. (2015) Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell 163:1400-12
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
Wu, Chuan; Yosef, Nir; Thalhamer, Theresa et al. (2013) Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496:513-7
Wu, Chuan; Pot, Caroline; Apetoh, Lionel et al. (2013) Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation. Proc Natl Acad Sci U S A 110:7802-7
Yosef, Nir; Shalek, Alex K; Gaublomme, Jellert T et al. (2013) Dynamic regulatory network controlling TH17 cell differentiation. Nature 496:461-8
Xiao, Sheng; Brooks, Craig R; Zhu, Chen et al. (2012) Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice. Proc Natl Acad Sci U S A 109:12105-10
Liu, Sue M; Sutherland, Andrew P R; Zhang, Zheng et al. (2012) Overexpression of the Ctla-4 isoform lacking exons 2 and 3 causes autoimmunity. J Immunol 188:155-62
Vignali, Dario A A; Kuchroo, Vijay K (2012) IL-12 family cytokines: immunological playmakers. Nat Immunol 13:722-8

Showing the most recent 10 out of 45 publications