The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization
and clearance of pathogens and subsequent host survival after natural infection with a
variety of microorganisms. Most currently available vaccines rely on the induction of longlived
protective humoral immune responses by memory B cells and plasma cells, underscoring
the importance of Abs in host protection. Ab responses against most antigens (Ags) require
interactions between B cells and CD4+ T helper cells, and it is now well recognized that
T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are
fundamentally required for the generation of T cell–dependent B cell responses. Perturbations
in the development and/or function of Tfh cells can manifest as immunopathologies,
such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and
molecular requirements underlying Tfh cell formation and maintenance will help to identify
molecules that could be targeted for the treatment of immunological diseases that are
characterized by insufficient or excessive Ab responses.