: Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system that is believed to result from erroneous activation of self-reactive T cells specific for myelin antigens. Experimental allergic encephalomyelitis (EAE) is an animal model for MS that is induced by immunization with myelin antigens. In the EAE-susceptible B10.PL strain, research has focused on T cells specific for the immunodominant epitope of myelin basic protein (MBP), AcMBP1-11. Our previous studies showed that the immunodominance of AcMBP1-11 is the product of immune tolerance induced by endogenous expression of MBP. We demonstrated using MBP-deficient mice that MBP121-150 is the most immunogenic region of MBP in the absence of tolerance. MBP121-150-specific T cells are subdominant in wild-type mice because central tolerance mechanisms eliminate most, but not all, of these T cells from the periphery. Using a MBP121-150-specific T cell receptor transgenic mouse model, we showed that the MBP121-150-specific T cells that escape central tolerance are pathogenic because they can be specifically triggered to induce EAE. New data presented here show that transgenic MBP121-150-specific T cells that reside in the periphery are prevented from causing spontaneous disease by regulatory T cells. Adoptive transfer of transgenic, naive MBP121-150-specific T cells into T cell deficient mice results in rapid and severe autoimmune disease. This autoimmunity is completely prevented by introducing CD4+ T cells. Surprisingly, the regulatory T cells do not inhibit expansion of the MBP-specific T cells in vivo after transfer or their migration to the brain. This proposal focuses on defining the phenotype (Aim 1) and mechanisms of action (Aim 2) of the regulatory T cells. We will test the hypothesis that regulatory T cells alter the cytokine milieu at sites of antigen presentation to inhibit activation of Th1 inflammatory T cells. Understanding how regulatory T cells prevent MBP-specific T cells from mediating disease is important for understanding the pathogenesis of MS and may provide insights into new therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043417-05
Application #
7037560
Study Section
Special Emphasis Panel (ZRG1-EI (02))
Program Officer
Utz, Ursula
Project Start
2002-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$281,271
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Cabbage, Sarah E; Huseby, Eric S; Sather, Blythe D et al. (2007) Regulatory T cells maintain long-term tolerance to myelin basic protein by inducing a novel, dynamic state of T cell tolerance. J Immunol 178:887-96
Perchellet, Antoine; Stromnes, Ingunn; Pang, Jennifer M et al. (2004) CD8+ T cells maintain tolerance to myelin basic protein by 'epitope theft'. Nat Immunol 5:606-14