Insights into the Role of Follicular Helper T Cells in Autoimmunity

Follicular helper T (T(FH)) cells are recently highlighted as their crucial role for humoral immunity to infection as well as their abnormal control to induce autoimmune disease. During an infection, naïve T cells are differentiating into T(FH) cells which mediate memory B cells and long-lived plasma cells in germinal center (GC). T(FH) cells are characterized by their expression of master regulator, Bcl-6, and chemokine receptor, CXCR5, which are essential for the migration of T cells into the B cell follicle. Within the follicle, crosstalk occurs between B cells and T(FH) cells, leading to class switch recombination and affinity maturation. Various signaling molecules, including cytokines, surface molecules, and transcription factors are involved in T(FH) cell differentiation. IL-6 and IL-21 cytokine-mediated STAT signaling pathways, including STAT1 and STAT3, are crucial for inducing Bcl-6 expression and T(FH) cell differentiation. T(FH) cells express important surface molecules such as ICOS, PD-1, IL-21, BTLA, SAP and CD40L for mediating the interaction between T and B cells. Recently, two types of microRNA (miRNA) were found to be involved in the regulation of T(FH) cells. The miR-17-92 cluster induces Bcl-6 and T(FH) cell differentiation, whereas miR-10a negatively regulates Bcl-6 expression in T cells. In addition, follicular regulatory T (T(FR)) cells are studied as thymus-derived CXCR5(+)PD-1(+)Foxp3(+) T(reg) cells that play a significant role in limiting the GC response. Regulation of T(FH) cell differentiation and the GC reaction via miRNA and T(FR) cells could be important regulatory mechanisms for maintaining immune tolerance and preventing autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we review recent studies on the various factors that affect T(FH) cell differentiation, and the role of T(FH) cells in autoimmune diseases.