Follicular helper T cells: new insights into mechanisms of autoimmune diseases

Autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, etc) are characterized by the production of autoantibodies against one's own cell components, resulting in the dysfunction of normal organs. At present, therapies for autoimmune diseases involve a variety of nonspecific antiinflammatory and immunosuppressive agents with significant side effects. Current studies have suggested that the germinal center (GC) may be the pathogenic hot spot for the production of autoantibodies in autoimmune disease. Events occurring in the GC-such as the selection of high-affinity B cells, proliferation of B cells, and differentiation of B cells into plasma cells-all depend on T cells. Follicular helper T (Tfh) cells are a recently identified T-cell subset, named for their location in GCs. Tfh cells are characterized by their signature transcription factor (B-cell lymphoma 6), surface molecules (CD40 ligand, chemokine [C-X-C] receptor 5, inducible T-cell costimulator, programmed cell death protein-1, etc), and cytokines (interleukin [IL]-21, IL-6, IL-10, etc). Through these signals, Tfh cells help B cells form GCs and drive B cells to differentiate into memory B cells and plasma cells that produce antibodies. However, uncontrolled generation of Tfh cells in the GCs or peripherals could lead to autoimmunity. Recent studies from our group and others have shown that Tfh cells are expanded in the peripheral blood of patients and in the lymphoid tissues of mice with lupus or rheumatoid arthritis and play an important role in promoting pathogenic autoantibody production. In this review, we summarize the latest immunologic findings regarding the characteristics and development of Tfh cells, their relation to other CD4(+) T-cell subsets, and the function of Tfh cells in normal immune response and autoimmune diseases. A clear understanding of the mechanisms of Tfh cell-mediated immunity and pathology may lead to the development of novel therapeutic targets in autoimmune diseases.