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Antibody production is an important feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Such humoral immunity has great longevity, often persisting for the host's lifetime. Long-lived humoral immunity depends on help provided by CD4⁺ T cells, namely T follicular helper (T_FH) cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. T_FH cells are stringently regulated, as aberrant T_FH cell activity is involved in immunopathologies such as autoimmunity, immunodeficiencies and lymphomas. The elucidation of the mechanisms that regulate T_FH cell differentiation, function and fate should highlight targets for novel therapeutics.