B and T Cells Driving Multiple Sclerosis: Identity, Mechanisms and Potential Triggers

Abstract

Historically, multiple sclerosis (MS) has been viewed as being primarily driven by T cells. However, the effective use of anti-CD20 treatment now also reveals an important role for B cells in MS patients. The results from this treatment put forward T-cell activation rather than antibody production by B cells as a driving force behind MS. The main question of how their interaction provokes both B and T cells to infiltrate the CNS and cause local pathology remains to be answered. In this review, we highlight key pathogenic events involving B and T cells that most likely contribute to the pathogenesis of MS. These include (1) peripheral escape of B cells from T cell-mediated control, (2) interaction of pathogenic B and T cells in secondary lymph nodes, and (3) reactivation of B and T cells accumulating in the CNS. We will focus on the functional programs of CNS-infiltrating lymphocyte subsets in MS patients and discuss how these are defined by mechanisms such as antigen presentation, co-stimulation and cytokine production in the periphery. Furthermore, the potential impact of genetic variants and viral triggers on candidate subsets will be debated in the context of MS.

Keywords: CD8+ T cells; Epstein-Barr virus; IFN-γ; T-bet+ B cells; Th1/Th17; genetic risk; germinal center; transmigration.

FIGURE 1

Model of the key pathogenic events involving human B- and T-cell subsets driving MS disease activity. In MS patients, B- and T-cells interact in the periphery and central nervous system (CNS) to contribute to disease pathogenesis. In this model, we put forward three important meeting points of pathogenic B and T cells that drive the disease course of MS. In secondary lymphoid organs, B-cell tolerance defects in MS patients allow EBV-infected B cells to escape from suppression by CD8⁺ and T regulatory (Treg) cells (1). Subsequently, these activated B cells enter germinal centers (GCs) and interact with follicular Th cells to further differentiate into pathogenic memory B cells. Under the influence of IFN-γ and IL-21, B cells develop into T-bet-expressing memory cells, which in turn activate Th effector cells such as Th17.1 (2). These subsets are prone for infiltrating the CNS of MS patients by distinct expression of chemokine receptors (CXCR3, CCR6), adhesion molecules (VLA-4) as well as pro-inflammatory cytokines. (3) Within the CNS, IFN-γ-, and GM-CSF-producing T cells and T-bet⁺ memory B cells probably come into contact in follicle-like structures, resulting in clonal expansion inflammation and demyelination. T-bet⁺ memory B cells further differentiate into plasmablasts/plasma cells to secrete high numbers of potentially harmful antibodies (oligoclonal bands).

FIGURE 2

Potential contribution of EBV and genetic risk factors to pathogenic B- and Th-cell development in MS patients. IFN-γ is a key player in autoreactive B- and Th-cell interaction and autoimmune germinal center (GC) formation in mice. In MS, we propose that EBV infection together with specific genetic risk variants promote the IFN-γ-mediated interplay between B and T cells within GCs. EBV directly infects naive B cells and mimic GC responses. EBV DNA can also bind to TLR7/9, and together with IFN-γ, induces T-bet⁺ memory B cells. Their interplay may be additionally stimulated by both B cell-intrinsic (IFN-γ sensitivity: IFNGR2; B cell receptor-antigen uptake: CBLB, SYK, CLEC16A; HLA class II pathway: CLEC16A, CIITA, IFI30; co-stimulation: CD80, CD86) and Th cell-intrinsic (surface receptors: IL2RA, IL7RA, IL12RB1; downstream molecules: TYK2, STAT3, STAT4) genetic risk variants. IL12R/IL-23R complexes trigger JAK2/STAT3-dependent RORγt and TYK2/STAT4-dependent T-bet expression in Th effector cells.