Epstein-Barr virus Peptide Presented by HLA-E is Predominantly Recognized by CD8bright Cells in multiple Sclerosis Patients

Pernille B Jørgensen,Per Höllsberg,Astrid H Livbjerg,Thor Petersen,Hans J Hansen,Steven Jacobson

doi:10.1371/journal.pone.0046120

Pernille B Jørgensen, Per Höllsberg + Show 4 more

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https://doi.org/10.1371/journal.pone.0046120

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Journal: PLoS ONE	Publication Date: Sep 25, 2012
Citations: 34	License type: CC BY 4.0

Affiliation: Aarhus University, Aarhus University Hospital

Abstract

Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection, but impaired immune suppression may be part of the disease pathogenesis. CD8+ T cells that are restricted by HLA-E exert an important immunoregulatory mechanism. To explore how EBV might interfere with immune regulation, we examined the expression of HLA-E and the frequency of CD8+ cells recognizing HLA-E, presenting either an EBV peptide from the BZLF1 protein or a signal sequence peptide from HLA-A2, in relapsing remitting (MS-RR), primary progressive (MS-PP) MS patients, and healthy controls (HC). Treatment with IFN-α or EBV increased HLA-E expression on CD4+ cells. However, only MS-PP had increased expression of HLA-E on resting CD4+ cells when compared with HC (p<0.005). CD8+ cells were divided into CD8bright and CD8dim cells by flow cytometry analyses. MS-RR had significantly fewer CD8dim cells than HC (p<0.003). Flow cytometry analyses were performed with HLA-E tetramers folded in the presence of the EBV or HLA-A2 peptide to identify HLA-E-interacting cells. MS-RR had increased frequency of CD8bright cells recognizing HLA-E/A2 (p = 0.006) and HLA-E/BZLF1 (p = 0.016). Conversely, MS-RR had fewer CD8dim cells that recognized HLA-E/BZLF1 (p = 0.001), but this could be attributed to the overall lower number of CD8dim cells in MS-RR. Whereas HLA-E/A2 was predominantly recognized by CD8dim cells, HLA-E/BZLF1 was predominantly recognized by CD8bright cells in MS-RR and MS-PP, but not in HC. As expected, HLA-E/A2 was also recognized by CD8-negative cells in a CD94-dependent manner, whereas HLA-E/BZLF1 was poorly recognized in all groups by CD8-negative cells. These data demonstrate that MS-RR patients have expanded their CD8bright cells recognizing HLA-E/BZLF1. Moreover, HLA-E/BZLF1 appears to be recognized by the immune system in a different manner than HLA-E/A2.

Highlights

Multiple sclerosis (MS) is an organ-specific disease of the central nervous system with an early inflammatory reaction [1]
To explore the mechanisms of how EpsteinBarr virus (EBV) might interfere with immune regulation in relapsing remitting (MS-RR) and primary progressive (MS-PP) MS patients as well as healthy controls (HC), we examined the expression of HLA-E and the frequency of CD8+ cells recognizing HLA-E
To address a possible role of HLA-E in MS, we initially examined its surface expression on resting CD4+ cells from healthy controls (HC), relapsing-remitting (MS-RR) and primary progressive (MS-PP) MS patients (Fig. 1A)

Summary

Introduction

Multiple sclerosis (MS) is an organ-specific disease of the central nervous system with an early inflammatory reaction [1]. Environmental, genetic and possibly stochastic events are thought to be important for the development of disease, the mechanisms are largely unknown. Based on clinical and sero-epidemiological observations, virus infection has been suspected to be involved. It has been controversial whether or not different viruses could induce a common trigger or whether few or perhaps only one virus would be able to do this. All MS patients, but not healthy controls, have seroconverted to EBV [5,6,7,8,9]. 86–99% of children with MS have detectable antibodies to EBV, only 64– 72% of healthy control children have seroconverted at a similar age [10,11,12]. EBV infection is consistent with a number of known epidemiological features of MS [2,3]

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