Interleukin 21 in immunity and autoimmunity

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 centres (GC). This study has reveals a critical role of IL-21 in the upregulation of Tfh signature molecules. Expression of ICOS was found to be necessary for optimal production of IL-21; indicative of interplay between two Tfh expressed molecules. We also demonstrate that IL-21's costimulatory capacity for T helper differentiation operates at the level of the TCR through Vav1 signalling that controls T cell helper function and survival. Tfh cells express uniquely high levels of the IL-21 receptor relative to other T cell subsets, which reflects an IL-21-driven autocrine loop that is important for the generation and function of Tfh cells, which in turn were critical for supporting primary and secondary T dependent antibody responses. This study reveals a previously unappreciated role for Tfh cells in the formation of the GC through a CD4+ T cell intrinsic requirement for responsiveness to IL-21. IL-2 and IL-21 are crucial growth factors for distinct T helper subsets with opposing regulatory and effector functions, respectively. Mice made genetically deficient in IL-2 or its high affinity receptor chain (CD25) suffer from a fatal autoimmune disease characterized by ulcerative colitis and haemolytic anaemia. The observed autoimmunity and associated splenomegally are thought to be caused, in part, by a loss of regulation of effector T cells due to a deficit in IL-2-dependent Foxp3 regulatory T cells. Since IL-21 is known to facilitate the development of a number of autoimmune diseases, the possible contribution of IL-21 to the autoimmune pathology observed in Il2-/- mice was investigated in this study. Our findings demonstrate that IL-21:IL-21R signalling contributes to the destruction of tissues attributed to autoimmunity in Il2-/- mice and suggests that IL-21-producing T cells are significant targets of immune system regulation.