EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2.
Symptomatic primary Epstein-Barr virus (EBV) infection and elevated humoral immune responses to EBV are associated with an increased risk of developing multiple sclerosis (MS). We explored mechanisms leading to this change in EBV-specific immunity in untreated patients with MS and healthy virus carriers matched for MS-associated HLA alleles. MS patients showed selective increase of T cell responses to the EBV nuclear antigen 1 (EBNA1), the most consistently recognized EBV-derived CD4(+) T cell antigen in healthy virus carriers, but not to other EBV-encoded proteins. In contrast, influenza and human cytomegalovirus-specific immune control was unchanged in MS. The enhanced response to EBNA1 was mediated by an expanded reservoir of EBNA1-specific central memory CD4(+) T helper 1 (Th1) precursors and Th1 (but not Th17) polarized effector memory cells. In addition, EBNA1-specific T cells recognized myelin antigens more frequently than other autoantigens that are not associated with MS. Myelin cross-reactive T cells produced IFN-gamma, but differed from EBNA1-monospecific cells in their capability to produce interleukin-2, indicative of a polyfunctional phenotype as found in controlled chronic viral infections. Our data support the concept that clonally expanded EBNA1-specific CD4(+) T cells potentially contribute to the development of MS by cross-recognition of myelin antigens.
Lünemann
Jan D
JD
Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065, USA.
Jelcić
Ilijas
I
Roberts
Susanne
S
Lutterotti
Andreas
A
Tackenberg
Björn
B
Martin
Roland
R
Münz
Christian
C
D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D003429:Cross Reactions; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000276:immunology / Q000821:virology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology*; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000209:etiology / Q000276:immunology* / Q000821:virology*; D004676:Myelin Basic Protein / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000821:virology
D000914:Antibodies, Viral; D001324:Autoantigens; D019309:Epstein-Barr Virus Nuclear Antigens; C508594:IL2 protein, human; D007074:Immunoglobulin G; D007376:Interleukin-2; D004676:Myelin Basic Protein; D007371:Interferon-gamma; C417029:EBV-encoded nuclear antigen 1