Characterization of antigen-specific CD8+ memory T cell subsets in peripheral blood of patients with multiple sclerosis

Abstract

Background: Increasing evidence indicates the importance of CD8⁺ T cells in autoimmune attack against CNS myelin and axon in multiple sclerosis (MS). Previous research has also discovered that myelin-reactive T cells have memory phenotype functions in MS patients. However, limited evidence is available regarding the role of CD8⁺ memory T cell subsets in MS. This study aimed to explore potential antigen-specific memory T cell-related biomarkers and their association with disease activity.

Methods: The myelin oligodendrocyte glycoprotein (MOG)-specific CD8⁺ memory T cell subsets and their related cytokines (perforin, granzyme B, interferon (IFN)-γ) and negative co-stimulatory molecules (programmed cell death protein 1 (PD-1), T- cell Ig and mucin domain 3 (Tim-3)) were analyzed by flow cytometry and real-time PCR in peripheral blood of patients with relapsing-remitting MS.

Results: We found that MS patients had elevated frequency of MOG-specific CD8⁺ T cells, MOG-specific central memory T cells (T_CM), MOG-specific CD8⁺ effector memory T cells (T_EM), and MOG-specific CD8⁺ terminally differentiated cells (T_EMRA); elevated granzyme B expression on MOG-specific CD8⁺ T_CM; and, on MOG-specific CD8⁺ T_EM, elevated granzyme B and reduced PD-1 expression. The Expanded Disability Status Scale score (EDSS) in MS patients was correlated with the frequency of MOG-specific CD8⁺ T_CM, granzyme B expression in CD8⁺ T_CM, and granzyme B and perforin expression on CD8⁺ T_EM, but with reduced PD-1 expression on CD8⁺ T_EM.

Conclusion: The dysregulation of antigen-specific CD8⁺ memory T cell subsets, along with the abnormal expression of their related cytokines and negative co-stimulatory molecules, may reflect an excessive or persistent inflammatory response induced during early stages of the illness. Our findings strongly suggest positive regulatory roles for memory T cell populations in MS pathogenesis, probably via molecular mimicry to trigger or promote abnormal peripheral immune responses. Furthermore, downregulated PD-1 expression may stimulate a positive feedback effect, promoting MS-related inflammatory responses via the interaction of PD-1 ligands. Therefore, these parameters are potential serological biomarkers for predicting disease development in MS.

Keywords: memory T cells; multiple sclerosis; oligodendrocyte glycoprotein; pentamer; peripheral blood mononuclear cells.