Suppression of autoimmune demyelinating disease by preferential stimulation of CNS-specific CD8 T cells using Listeria-encoded neuroantigen

Farah R Itani,Katherine N Gibson-Corley,Ashley A Brate,John T Harty,Sushmita Sinha,Lecia L Pewe,Nitin J Karandikar

doi:10.1038/s41598-017-01771-8

Farah R Itani, Katherine N Gibson-Corley + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-01771-8

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Journal: Scientific Reports	Publication Date: May 8, 2017
Citations: 9	License type: open-access

Affiliation: University of Iowa

Abstract

CD8 T-cells predominate in CNS lesions of MS patients and display oligoclonal expansion. However, the role of myelin-specific CD8 T-cells in disease remains unclear, with studies showing protective and pathogenic roles in EAE. We 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 activation. To probe the nature of the CD8 response elicited by endogenously presented myelin antigens in vivo, we developed a novel approach utilizing infection with Listeria monocytogenes (LM) encoding proteolipid protein peptide (PLP) amino acids 178-191 (LM-PLP). LM-PLP infection preferentially induced PLP-specific CD8 T-cell responses. Despite the induction of PLP-specific CD8 T-cells, LM-PLP infection did not result in disease. In fact, LM-PLP infection resulted in significant amelioration of PLP178-191-induced EAE. Disease suppression was not observed in mice deficient in CD8 T-cells, IFN-γ or perforin. DTH responses and CNS infiltration were reduced in protected mice, and their CD4 T-cells had reduced capacity to induce tissue inflammation. Importantly, infection with LM-PLP ameliorated established disease. Our studies indicate that CD8 T-cells induced by endogenous presentation of PLP178-191 attenuate CNS autoimmunity in models of EAE, implicating the potential of this approach as a novel immunotherapeutic strategy.

Highlights

Multiple sclerosis (MS), the most common neurologic disease of young adults, is a T cell-mediated demyelinating disease of the central nervous system (CNS) in which autoreactivity results in progressive impairment in neurologic function[1]
Infection with an attenuated strain of L. monocytogenes encoding for proteolipid protein (PLP)-178-191 generates CNS-specific CD8 T cells, with no evidence of pathogenicity
Almost all of these studies either used transgenic models with CNS-expressed foreign antigens as the target or employed immunization techniques that depended on cross-presentation for the induction of CD8 T cell responses

Summary

Introduction

Multiple sclerosis (MS), the most common neurologic disease of young adults, is a T cell-mediated demyelinating disease of the central nervous system (CNS) in which autoreactivity results in progressive impairment in neurologic function[1]. Different subsets of CD8 T cells have been described as pathogenic effectors and/or regulators of the immune response in EAE Studies have utilized both myelin-targeted and non-myelin antigen-driven systems to examine the pathogenic potential of CD8 T cells (reviewed in refs 3, 4). We have shown disease suppressive function in myelin oligodendrocyte glycoprotein (MOG) peptide 35–55-induced CD8 T cells in the B6 model as well as PLP178-191-induced CD8 T cells in both B6 and SJL mice[10, 11, 14] In these systems the response-inducing antigen was administered exogenously in the form of a CFA-containing immunization (which is the standard protocol for EAE induction) or the addition of these peptides to in vitro cultures. Induction of CD8 T cell responses would involve processing and cross-presentation of the antigens[15]

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