Follicular Helper CD4+ T Cells, Follicular Regulatory CD4+ T Cells, and Inducible Costimulator and Their Roles in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Follicular helper CD4 + T (TFH) cells are a specialized subset of effector T cells that play a central role in orchestrating adaptive immunity. TFH cells mainly promote germinal center (GC) formation, provide help to B cells for immunoglobulin affinity maturation and class‐switch recombination of B cells, and facilitate production of long‐lived plasma cells and memory B cells. TFH cells express the nuclear transcriptional repressor B cell lymphoma 6 (Bcl‐6), the chemokine (C‐X‐C motif) receptor 5 (CXCR5), the CD28 family members programmed cell death protein‐1 (PD‐1) and inducible costimulator (ICOS) and are also responsible for the secretion of interleukin‐21 (IL‐21) and IL‐4. Follicular regulatory CD4+ T (TFR) cells, as a regulatory counterpart of TFH cells, participate in the regulation of GC reactions. TFR cells not only express markers of TFH cells but also express markers of regulatory T (Treg) cells containing FOXP3, glucocorticoid‐induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte antigen 4 (CTLA‐4), and IL‐10, hence owing to the dual characteristic of TFH cells and Treg cells. ICOS, expressed on activated CD4 + effector T cells, participates in T cell activation, differentiation, and effector process. The expression of ICOS is highest on TFH and TFR cells, indicating it as a key regulator of humoral immunity. Multiple sclerosis (MS) is a severe autoimmune disease that affects the central nervous system and results in disability, mediated by autoreactive T cells with evolving evidence of a remarkable contribution from humoral responses. This review summarizes recent advances regarding TFH cells, TFR cells, and ICOS, as well as their functional characteristics in relation to MS.