A fundamental role for Interleukin-21 in germinal center antibody responses (38.21)

Abstract T cell help to B cells is a fundamental property of adaptive immunity, yet only recently have many of the cellular and molecular mechanisms of T cell help emerged. T follicular helper (TFH) cells are the CD4+ T helper cells that provide cognate help to B cells for high affinity antibody production in germinal centers (GC), and have recently been shown to give rise to lymphoid reservoirs of antigen specific memory T cells. TFH cells produce IL-21 and we have shown that IL-21 is necessary for GC formation. However the central role of IL-21 in GC formation reflected its effects on CD4+ T cells rather than on B cells. Furthermore, bone marrow chimeras confirm that IL-21R-deficient B cells are capable of mounting an effective IgG1 response to T dependent antigen. Using an antigen specific model where TCR transgenic CD4 T cells specific for the ovalbumin peptide were introduced into IL-21R-/- mice, we show that IL-21 responsiveness by T cells was important for optimal primary and secondary antibody responses. IL-21 also proved indispensable for affinity maturation of ova-specific antibodies in the GC. This study reveals a previously unappreciated role for TFH cells in the formation of the GC and isotype switching through a CD4+ T cell intrinsic requirement for responsiveness to IL-21.