The role of IL-4 derived from follicular helper T (TFH) cells and type 2 helper T (TH2) cells

IL-4 is known to be the quintessential regulatory cytokine, playing a role in a vast number of immune and non-immune functions. This cytokine is commonly secreted by type 2 helper T (T(H)2) cells and follicular helper T (T-FH) cells after antigenic sensitization. T(H)2 cells have been classically thought to be the major contributor to B-cell help as a source of IL-4 responsible for class-switch recombination to IgG1 in mice (IgG4 in humans) and to IgE in mice and humans. Recent in vivo observations have shown that IgE and IgG1 antibody responses are mainly controlled by IL-4-secreting T-FH cells but not by classical T(H)2 cells. IL-4 is distinctively regulated in these two T-cell subsets by the GATA-3-mediated HS2 enhancer in T(H)2 cells and the Notch-mediated conserved non-coding sequence 2 (CNS-2) enhancer in T-FH cells. Moreover, the IL-4 derived from T-FH cells has an essential role in germinal center (GC) formation in the secondary lymphoid organs during humoral immune responses.