Tfh

T follicular helper cells (Tfh) are a specialized subset of CD4+ T cells that provide help to B cells during antibody responses. They localize to B cell follicles and germinal centers in secondary lymphoid organs, guided by the chemokine receptor CXCR5. They characteristically express high levels of PD-1, ICOS, and the transcription factor Bcl6, and secrete the cytokine IL-21 as a key effector signal, with IL-4 contributing in some contexts.

Development and differentiation of Tfh cells begin in T cell zones after antigen presentation by dendritic cells. Cytokines such as IL-6 and IL-21, along with ICOS-ICOSL signaling, promote the Tfh gene program. Bcl6 acts as the master regulator, promoting Tfh features while repressing alternate helper lineages. Stable T-B cell interactions, supported by the SAP adaptor and SLAM family receptors, consolidate Tfh identity and entry into germinal centers.

Function within germinal centers involves providing CD40 ligand and cytokines to B cells, promoting somatic hypermutation, affinity maturation, and class-switch recombination. Tfh cells help select high-affinity B cell clones and drive differentiation into memory B cells and plasma cells, shaping both the quality and durability of humoral immunity. The spatial organization of Tfh cells in light zones relative to B cells influences the selection process.

Clinical relevance is seen with circulating Tfh-like cells in blood, which can reflect vaccine responses. Dysregulation of Tfh development or function has been linked to autoimmune diseases such as systemic lupus erythematosus, chronic infections, and impaired antibody responses. Therapeutic strategies targeting Tfh–B cell interactions, including ICOS-ICOSL or CD40-CD40L pathways, are under investigation.