Proinflammatory CD20+ T Cells in the Pathogenesis of Multiple Sclerosis

Marina R. von Essen; Cecilie Ammitzbøll; Rikke H. Hansen; Eva R. S. Petersen; Oskar McWilliam; Hanne V. Marquart; Peter Damm; Finn Sellebjerg

Disclosures

Brain. 2019;142(1):120-132. 

In This Article

Abstract and Introduction

Abstract

With the discovery that the highly effective anti-CD20 antibody therapies developed to deplete CD20+ B cells deplete CD20+ T cells equally well, a great interest in the biological properties of CD20+ T cells has emerged. In this study we show that CD20+ T cells have a proinflammatory Th1/Tc1 phenotype with a high proliferative capacity to CNS antigens. We also found that the percentage of CD20+ T cells is increased in the blood of patients with multiple sclerosis and are enriched in the CSF of the patients. Furthermore, we found a positive correlation between CD20+ T cells in the CSF and multiple sclerosis disease severity and see that regulation of CD20+ T cells likely contributes to the positive treatment effect of the multiple sclerosis treatment alemtuzumab. These data represent an important contribution to the understanding of the nature of CD20+ T cells and strongly suggests a role of CD20+ T cells in the pathogenesis of multiple sclerosis.

Introduction

Multiple sclerosis is a chronic inflammatory disease of the CNS characterized by T cell-mediated demyelination and axonal damage (Compston and Coles, 2008; Sospedra and Martin, 2016). Within the past decade, it has become clear that B cells also play a role in multiple sclerosis pathogenesis (Sospedra and Martin, 2016) and the development of B cell depleting therapy with rituximab, ofatumumab and ocrelizumab has strengthened this perception (Hauser et al., 2008; Kappos et al., 2011). The target of these therapies is CD20 expressed on the cellular surface of most B cells. Recently, a subpopulation of T cells expressing CD20 has also been described; and like B cells these T cells are depleted from the blood by the anti-CD20 antibody therapies (Wilk et al., 2009; Palanichamy et al., 2014; Schuh et al., 2016) suggesting that depletion of CD20+ T cells may contribute to the treatment effects.

The implication of CD20+ T cells in multiple sclerosis remains to be fully elucidated, and the biological role of the CD20 molecule is unclear. CD20 is proposed to function as part of a complex that forms or controls calcium entry into the cells (Parolini et al., 2012). Influx of extracellular Ca2+ in T cells ensures progression of calcium-depending processes such as cell activation, proliferation, apoptosis and NFAT/NFκB-induced production of cytokines such as IFNγ and TNFα (Christo et al., 2015). Accordingly, previous studies have shown increased Ca2+ influx (Wilk et al., 2009), increased susceptibility to apoptosis (Wilk et al., 2009), and increased production of IFNγ and TNFα (Holley et al., 2014; de Bruyn et al., 2015; Schuh et al., 2016) in CD20+ T cells, as compared to CD20 T cells. This immunological profile of CD20+ T cells suggests that CD20+ T cells play a central role in tissue inflammation.

The purpose of this study was therefore to elucidate a potential role of CD20+ T cells in the pathogenesis of multiple sclerosis and to thoroughly characterize the immunological functions of this cell population.

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