Document Type

Dissertation

Date of Degree

Summer 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In

Immunology

First Advisor

Nitin J. Karandikar

Second Advisor

Vladimir P. Badovinac

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) with characteristic multifocal lesions or ‘ plaques’ of demyelination mainly in the white matter of the brain ( involving cerebral cortex, cerebellar, brain stem and spinal cord). These MS plaques vary in size and shape, and are composed of infiltrates of lymphocytes and macrophages - which contain myelin debris. CD8 T cells are more prevalent in CNS lesions and display oligoclonal expansion. However, their role in disease remains unclear with studies showing both protective and pathogenic roles for myelin-specific CD8 T cells in the experimental autoimmune encephalomyelitis (EAE) model. Our studies have demonstrated a disease-suppressive function for CNS-specific CD8 T cells in a model where the antigen is exogenously administered in vivo and used for in vitro CD8 activation. My studies focus on probing the nature of the CD8 response elicited by endogenously presented myelin antigens in vivo utilizing a novel approach, infection with Listeria monocytogenes (LM) encoding for myelin proteolipid protein peptide PLP178-191 (LM-PLP).

I show that LM-PLP infection preferentially induces PLP-specific CD8, but not CD4, T cell responses. Despite this, infection does not result in autoimmunity. In fact, routinely induced EAE is significantly ameliorated in LM-PLP-infected mice, compared to controls. Disease suppression is dependent on the presence of CD8 T cells, and the effector molecules IFN-g and perforin. CNS T cell infiltration and inflammatory responses are reduced in LM-PLP-protected mice, and CD4 T cells from LM-PLP-protected mice are less inflammatory than those from controls. Importantly, infection with LM-PLP ameliorates already established disease. My studies indicate that myelin-specific CD8 T cells induced by endogenous presentation of antigen attenuate CNS autoimmunity in multiple mouse models of EAE, implicating the potential of this approach as a novel immunotherapeutic strategy.

Keywords

autoimmunity, CD8 T cells, central nervous system, experimental autoimmune encephalomyelitis, Listeria monocytogenes, Multiple sclerosis

Pages

xv, 158 pages

Bibliography

Includes bibliographical references (pages 140-158).

Copyright

Copyright © 2017 Farah R. Itani

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