Epstein-Barr virus peptide presented by HLA-E is predominantly recognized by CD8(bright) cells in multiple sclerosis patients.
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 CD8(bright) and CD8(dim) cells by flow cytometry analyses. MS-RR had significantly fewer CD8(dim) 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 CD8(bright) cells recognizing HLA-E/A2 (p=0.006) and HLA-E/BZLF1 (p=0.016). Conversely, MS-RR had fewer CD8(dim) cells that recognized HLA-E/BZLF1 (p=0.001), but this could be attributed to the overall lower number of CD8(dim) cells in MS-RR. Whereas HLA-E/A2 was predominantly recognized by CD8(dim) cells, HLA-E/BZLF1 was predominantly recognized by CD8(bright) 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 CD8(bright) 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.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Pernille B
PB
Jørgensen
Astrid H
AH
Livbjerg
Hans J
HJ
Hansen
Thor
T
Petersen
Per
P
Höllsberg
D000328:Adult; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology*; D000097625:HLA-E Antigens
D015395:Histocompatibility Antigens Class I; D010455:Peptides; D014764:Viral Proteins; D000097625:HLA-E Antigens