Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that is believed to have an autoimmune etiology. It is the most common neurological disease in young adults. The pathogenesis of MS is not well understood and this has limited the ability to develop effective therapies. Experimental allergic encephalomyelitis (EAE), a widely used animal model for MS, has provided many insights into the activity of myelin-specific CD4+ T cells that can mediate CNS autoimmune disease. However, the clinical signs and pathology seen in MS patients is very heterogeneous and only a subset of the characteristics of MS patients is reproduced in classical CD4+ T cell-mediated EAE models. This observation suggests that new models are needed to investigate the diverse mechanisms contributing to this disease. Our laboratory developed a new EAE model based on the activity of myelin basic protein (MBP)- specific CDS+ T cells. Transfer of activated MBP-specific T cells induces autoimmune disease that recapitulates some of the clinical signs and pathology seen in MS patients that are not typically seen in classic EAE. We generated T cell receptor transgenic models of these CDS+ T cells and found that an unusual form of tolerance allows CDS+ T cells expressing a high affinity T cell receptor for MBP to escape tolerance and populate the peripheral repertoire. Interestingly, this tolerance can be broken by viral infection. In this application, we will investigate the molecular mechanisms underlying both the CDS+ T cell tolerance and the loss of tolerance due to infection in this model. We will also identify the CNS cells that present the MHC class l-associated MBP epitope to the CDS+ T cells and the consequences of interaction between the CDS+ T cells and CNS cells during disease. Finally, we will determine if the CDS+ and CD4+ T cells subsets utilize different tissue homing molecules to infiltrate the CNS and compare the CNS damage mediated by the CDS+ T cells to the pathology mediated by myelin-specific CD4+ T cells that induce EAE in the same mouse strain. The over-arching hypothesis guiding these studies is that myelin-specific CDS+ T cells differ from CD4+ T cells in the mechanisms used to escape tolerance, in their recognition of targets cells in the CNS and in the pathologic consequences of antigen recognition in the CNS. Testing this hypothesis will determine whether there are unique aspects of CNS autoimmune disease mediated by myelin-specific CDS+ T cells, a subject with significant clinical relevance to human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072737-14
Application #
8013872
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2007-02-15
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
14
Fiscal Year
2011
Total Cost
$375,541
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Ji, Qingyong; Castelli, Luca; Goverman, Joan M (2013) MHC class I-restricted myelin epitopes are cross-presented by Tip-DCs that promote determinant spreading to CD8⁺ T cells. Nat Immunol 14:254-61
Pierson, Emily; Simmons, Sarah B; Castelli, Luca et al. (2012) Mechanisms regulating regional localization of inflammation during CNS autoimmunity. Immunol Rev 248:205-15
Goverman, Joan M (2011) Immune tolerance in multiple sclerosis. Immunol Rev 241:228-40
Ji, Qingyong; Perchellet, Antoine; Goverman, Joan M (2010) Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs. Nat Immunol 11:628-34
Goverman, Joan (2009) Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9:393-407
Stromnes, Ingunn M; Cerretti, Lauren M; Liggitt, Denny et al. (2008) Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med 14:337-42
Perchellet, Antoine; Brabb, Thea; Goverman, Joan M (2008) Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein. Proc Natl Acad Sci U S A 105:14040-5