CD4 T Cell Responses to the Epstein-Barr Virus are Reduced by Disease-modifying Therapies in Patients with Multiple Sclerosis
Natalia Drosu1, Philippe-Antoine Bilodeau1, Joao Vitor Mahler1, Monique Anderson1, Takahisa Mikami1, Natasha Bobrowski-Khoury1, Michael Levy1
1Massachusetts General Hospital
Objective:
To investigate the impact of disease-modifying therapies (DMTs) on CD4 T cell responses to Epstein-Barr virus (EBV) antigens in patients with multiple sclerosis (MS).
Background:
EBV infection is strongly associated with MS risk. DMTs are effective in treating MS and have been demonstrated to reduce CD8 T cell responses to EBV - particularly anti-CD20, teriflunomide and dimethyl fumarate. However, their effect on CD4 T cell responses to EBV remains less clear, despite the potential importance of these cells in MS immunopathology.
Design/Methods:
We conducted a cross-sectional study of 60 relapsing-remitting MS patients: 23 treatment-naïve and 37 on various DMTs (22 anti-CD20, 8 natalizumab, 4 dimethyl fumarate, 3 others). CD4 T cell responses to EBV latent and lytic antigens were assessed separately using IFN-γ ELISPOT assays, measuring the number of spot-forming cells (SFCs).
Results:
Treatment-naïve MS patients showed a predominant CD4 T cell response to EBV lytic antigens, with 10-fold higher median SFCs compared to latent antigens (p<0.001). DMT-treated MS patients, especially those on anti-CD20 therapies, exhibited significantly reduced responses to lytic antigens. The anti-CD20 group showed a 75% decrease in median SFCs for lytic antigens (p<0.001), while responses to latent antigens remained unchanged. Other DMTs also reduced EBV antigen responses, similar to anti-CD20 therapies. Notably, natalizumab was the exception, showing no significant reduction in responses to latent or lytic EBV antigens.
Conclusions:
DMTs, particularly anti-CD20 therapies, significantly reduce CD4 T cell responses to EBV lytic antigens in MS patients, while responses to latent antigens remain largely unchanged. This specific effect on lytic antigen responses may contribute to the therapeutic efficacy of these treatments, possibly by reducing EBV-driven CD4 T cell help to myelin-targeting CD8 T cells. Our findings shed light on how DMTs affect EBV-specific immune responses in MS, pointing to possible new treatment approaches targeting EBV lytic antigen presentation.
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