T follicular helper (Tfh) cells are a regulatory class of specialized effector T helper cells that are essential in the development of antigen-specific effector and memory B cell responses. Tfh cells are found enriched within the edges of the B cell zones of secondary lymphoid organs such as the lymph nodes, spleen, and Peyer’s patches. These cells regulate humoral immunity, particularly germinal center reactions, and play a role in the development of long-term antibody responses. Upon antigen-specific stimulation, Tfh cells migrate to the follicular regions of secondary lymphoid tissues, where they form stable contacts with antigen-primed B cells and release IL-4, IL-10, IFN gamma, and IL-21 to stimulate mature B cells into forming germinal centers and undergoing antibody class-switching.
Tfh cells are defined phenotypically by high expression of CXCR5 (CD185, CXCL13 receptor), Bcl-6, and IL-21 along with low CCR7 (CD197) expression. Activated CXCR5hiCCR7lo T cells migrate to the B cell follicles in response to high levels of CXCL13, which is secreted by follicular stromal cells. Nevertheless, Tfh cells require IL-6, IL-21, and B cell interaction for complete development. A key transcription factor involved in this differentiation is Bcl-6, which regulates the changes in CXCR5 and CCR7 expression required for T cell migration to the follicle. Moreover, Bcl-6 promotes Tfh cell development by repressing Blimp-1, ROR gamma t, T-bet, and GATA3, as well as several miRNAs. Interestingly, Bcl-6 also plays a critical role in germinal center B cell differentiation. Because they mediate antigen-specific B cell immunity, Tfh cells have been linked to diseases such as angioimmunoblastic T cell lymphoma, as well as autoimmune disorders including systemic lupus erythematosus and Sjogren's syndrome.