Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins

• Published in: Multiple sclerosis 2016-03, Vol.22 (3), p.279-291
• Main Authors: van Nierop, Gijsbert P, Mautner, Josef, Mitterreiter, Johanna G, Hintzen, Rogier Q, Verjans, Georges MGM
• Format: Article
• Language: English
• Subjects: Adult; alpha-Crystallin B Chain - immunology; Antigen-presenting cells; Antigens; Autoantigens; Autoantigens - immunology; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell lines; Cerebrospinal fluid; Crystallin; Enzyme-Linked Immunosorbent Assay; Epstein-Barr virus; Epstein-Barr Virus Infections - immunology; Female; Herpesvirus 4, Human; Histocompatibility antigen HLA; Humans; Lymphocytes B; Lymphocytes T; Male; Middle Aged; Multiple sclerosis; Multiple Sclerosis - cerebrospinal fluid; Multiple Sclerosis - immunology; Neurological diseases; Patients; Pneumoviridae; Proteins; Real-Time Polymerase Chain Reaction; T cell receptors; Viral Proteins - immunology
• ISSN: 1352-4585; 1477-0970
• DOI: 10.1177/1352458515588581

Background: The association between Epstein-Barr virus (EBV) and multiple sclerosis (MS) may involve intrathecal EBV-specific T-cell responses targeting the virus or indirectly, autoantigens. Objective: Compare the prevalence and fine-specificity of EBV-specific T-cells in the cerebrospinal fluid (CSF) of patients with MS (n = 12), clinically-isolated syndrome (CIS) (n = 17) and other neurological diseases (OND) (n = 13). Methods: Intrathecal EBV-specific T-cell reactivity was assayed using CSF-derived T-cell lines (CSF-TCL) and autologous EBV-transformed B-cells (autoBLCL) as antigen-presenting cells (APC). EBV proteins recognized by autoBLCL-specific CD8 T-cells were identified using human leukocyte antigen class I (HLA-I)-negative monkey cells as artificial APC, co-transfected with 59 different EBV genes and the corresponding patient’s HLA-I alleles that were involved in autoBLCL T-cell reactivity. Reactivity towards the MS-associated autoantigen αB-crystallin (CRYAB) was determined analogously. Results: CSF-TCL from CIS and MS patients had significantly higher frequencies of autoBLCL-reactive CD4 T-cells, compared to the OND patients. CIS patients also had significantly higher autoBLCL-reactive CD8 T cells, which correlated with reactive CD4 T-cell frequencies. AutoBLCL-specific CD8 T-cell responses of four CSF-TCL analyzed in detail were oligoclonal and directed to lytic EBV proteins, but not CRYAB endogenously expressed by autoBLCL. Conclusions: Enhanced intrathecal autoBLCL-specific T-cell reactivity, selectively directed towards lytic EBV proteins in two CSF-TCL, suggested a localized T-cell response to EBV in patients with MS. Our data warrant further characterization of the magnitude and breadth of intrathecal EBV-specific T-cell responses in larger patient cohorts.