Members of a subfamily of the type 1 four-helix-bundle cytokines with receptors sharing the common gamma (cγ) chain including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 have distinct activities on the differentiation of effector, memory, and regulatory T cells 12. Furthermore, IL-2, IL-4, and IL-21 serve distinct roles in control of B cell development and differentiation to antibody producing cells. We and others recently reported that both IL-2 and IL-21 are essential for maintenance of CD8 T cells and control of chronic viral infection, while both cytokines are dispensable for expansion and contraction of CD8 T cells during acute and resolved viral infection 34567.
While IL-21 has been implicated in cross-regulation of Th17 cells and inducible regulatory T cells (Treg) in vitro, development of Th17 and Treg cells and consequently organ-related autoimmune disease remain unaffected in IL-21R-deficient mice in vivo 89. In contrast, we now found that IL-21 can potently inhibit proliferation and function of inducible and natural Treg cells in models of T cell transfer colitis, viral infection, and asthma. Increased numbers of Tregs in IL-21R-deficient mice offer an explanation for suppression of Th2-mediated asthma and susceptibility to chronic viral infection described in the knockout mice 510.
Furthermore, the importance of IL-21 for B cell and antibody responses has been well established. Recently, it has been suggested that IL-21 is crucial for development of T follicular helper cells (Tfh) and defective B cell responses in IL-21R-deficient mice are due to the absence of Tfh cells. However, we found that germinal center development and antibody responses were severely impaired in mice that lack IL-21R specifically on B cells suggesting that IL-21 regulates germinal center responses in a B cell intrinsic manner 11. In addition, we have shown that requirement of IL-21 for a B cell response is overcome by immunization with particulate antigens containing TLR7/8 ligands (such as viral RNS). These data demonstrate that innate pathogen patterns (PAMPs) and Th cell derived signals co-operate in the induction of optimal IgG responses. Interestingly, in contrast to follicular B cell responses, IL-21 has been shown to negatively regulate marginal zone (MZ) B-cell survival and antibody production to Streptococous pneumonia 12.