Emerging Role of Follicular T Helper Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Abstract

Multiple sclerosis is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse models that Th17, B cells, and follicular T helper (TFH) cells contribute to disease. This review article describes the literature that identifies mechanisms by which Th17, TFH, and B cells cooperatively drive disease activity in MS and EAE. The curation of this literature has identified that CNS-infiltrating TFH cells act with TH17 cell to contribute to an inflammatory B cell response in neuroinflammation. This demonstrates that TFH cells and their products are promising targets for therapies in MS.shown to be critical for effective B-cell activity in many different models of infection and vaccination. These cells have also been shown to be associated with many different autoimmune diseases including Systemic Lupus Erythematosus (SLE) 15 , Rheumatoid Arthritis (RA) 16 , and Multiple sclerosis 17 .Currently, there is not a complete and though understanding of how naïve CD4+ helper T cells differentiate into mature TFH cells. However, many studies have provided some inroads on to the mechanisms involved in TFH differentiation. These studies have indicated that proper differentiation is "multistage and multifactorial" [18][19] . The cytokines IL-6 and IL-21 are important for effective differentiation 20-21 . IL-6 signaling through STAT3 and STAT1 leads to BCL6 expression in T cells in vitro 22 and IL-6 leads to IL-21 production. IL-21 can also lead to BCL6 expression in T cells though there appears to be substantial overlap in signaling between these cytokines 21 . Further complicating the process, experiments in knockout mice demonstrate that they are not the only factor involved [23][24] . There is also evidence that the quality and duration of TCR/MHCII interaction during initial stimulation can affect whether a naïve T cell will differentiate into a TFH cell. Certain models demonstrate that T cells with a high affinity TCR are more likely to differentiate into TFH cells 25 .Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

Ectopic Lymphoid Follicles in Multiple Sclerosis: Centers for Disease Control?

“…T H 17 cells are thought to be the primary T helper subset driving MS pathogenesis. Initially described in EAE models, this hypothesis is also supported in humans as T H 17 are elevated in the CSF of MS patients, specifically during relapse (91). Several T H 17-associated cytokines are associated with MS pathology.…”

“…LTo cells also begin to express intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in order to aid in immune cell retention upon entry. Finally, LTo cells will differentiate into FDCs, fibroblastic reticular cells (FRCs), and marginal reticular cells, which comprise the stromal reticular network (89,91,92).…”

“…Partially due to their formation being initiated by inflammation, eLFs can form and dissipate quickly. As a direct consequence of this transient nature, eLFs can display significant organizational and cellular heterogeneity ranging from small and disorganized aggregates of B and T cells to highly organized structures containing compartmentalized T and B cell zones, HEVs, FDCs, and a developed stromal reticular network (10,11,80,90,91). It is important to note, however, that once the reticular network has formed and an eLF has reached an advanced state of maturation, eLFs become fairly stable and are less likely to dissipate (94).…”

“…Importantly, these samples are typically obtained at later stages of disease when inflammation is possibly less pronounced (89). Therefore, while heterogeneous observations between patients regarding cellular composition and structural organization can partly be explained by the transient nature of eLFs, it is more likely a consequence of differences in disease stage and varying degrees of residual CNS inflammation between patients (91).…”

“…T FH cells are broadly identified as CXCR5 + PD-1 + BCL6 + ICOS + and their effector function is primarily associated with the secretion of IL-21 (91). This subset is most strongly linked to GC B cell responses and has only recently been included as a diseaserelevant subset in MS and other disease conditions (133,134).…”