Swine IL-21 (Interleukin-21) is a cytokine of the common γ chain (γc) family that plays a central role in regulating adaptive immune responses in pigs (Sus scrofa). IL-21 is produced primarily by activated CD4⁺ T cells, particularly T follicular helper (Tfh) cells and Th17 cells, following antigen stimulation. It signals through the IL-21 receptor (IL-21R) in association with the common γ chain, activating downstream JAK/STAT pathways—predominantly STAT3—to regulate gene expression in B cells, T cells, and natural killer (NK) cells. IL-21 promotes B cell proliferation, plasma cell differentiation, immunoglobulin class switching, and antibody production, while enhancing CD8⁺ T cell cytotoxic activity and NK cell function. In healthy swine, basal IL-21 expression is generally low but increases during infection, vaccination, and immune activation. Altered IL-21 responses have been associated with porcine reproductive and respiratory syndrome virus (PRRSV), swine influenza virus, African swine fever virus (ASFV), and enteric infections, where effective T cell–dependent antibody responses are critical for protection. Pigs serve as important translational models for human immunology, vaccine development, and mucosal immune research due to similarities in immune system organization. In veterinary and biomedical research, swine IL-21 is studied as a biomarker of T cell–dependent B cell help and humoral immunity and as a key regulator of adaptive immune responses in infectious disease and vaccination models.