The CXCL13–CXCR5 axis and follicular cytotoxic T cells: Linking T–B crosstalk in autoimmune diseases

Follicular cytotoxic T (Tfc) cells, a distinct subset of CXCR5⁺CD8⁺ T lymphocytes, have recently gained attention for their dual roles in cytotoxicity and immune regulation within lymphoid follicles. Unlike conventional cytotoxic T cells, Tfc cells exhibit a follicular phenotype that enables close B cell interaction, influencing germinal center dynamics and antibody production. Accumulating evidence suggests that Tfc cells participate in a wide spectrum of pathological processes, including chronic infection, tumor immunity, and autoimmune diseases. In autoimmune settings, such as multiple sclerosis (MS), myasthenia gravis (MG), and rheumatoid arthritis (RA), aberrant CXCR5/CXCL13 signaling axis activation may promote excessive T-B cell collaboration and persistent autoantibody generation. However, the functional significance of Tfc cells in these conditions remains incompletely understood. CXCR5/CXCL13 axis disruption or modulation alters Tfc and Tfh cell activity, underscoring its central role in sustaining autoimmune inflammation. This review summarizes the current knowledge of Tfc cell phenotypes, signaling pathways, and their emerging roles across autoimmune diseases, with a particular focus on the CXCR5/CXCL13 axis as a potential therapeutic target. Understanding how this pathway regulates Tfc differentiation and function may open new avenues for precision immunotherapy in autoimmune disorders.