IL-21 is a member of the common gamma chain (gammac)-dependent cytokine family that mediates its cellular effects through the functional receptor that consists of gammac and IL-21Ralpha chain. However, the regulation of the IL-21Ralpha chain has not been precisely defined. The most important effect of IL-21 is to cooperatively with IL-4 promote T cell-dependent Ab responses. Paradoxically, IL-21 has been shown to deliver pro-apoptosic signals and variably support B cell proliferation in vitro. Moreover, it was unclear how IL-21 and IL-4, both produced by activated T cells, individually and jointly influence B cell responses.Using a novel mAb to IL-21R, the IL-21R was detected during T and B cell development such that this receptor is expressed by all mature lymphocytes. The IL-21R was further regulated during peripheral B cell development and upregulated after B and T activation. Functional studies demonstrated that IL-21 substantially inhibited proliferation and induced Bim-dependent apoptosis for LPS or CpG DNA-activated B cells. In contrast, IL-21 induced both co-stimulation and apoptosis for anti-CD40 stimulated B cells whereas IL-21 primarily co-stimulated B cells activated by anti-IgM or anti-IgM plus anti-CD40. Upon blocking apoptosis using C57BL/6 Bim-deficient or Bcl-2 transgenic B cells, IL-21 readily co-stimulated responses to anti-CD40 while proliferation to LPS was still inhibited. Engagement of CD40 prevented the inhibitory effect by IL-21 for LPS-activated B cells. IL-4 exhibited redundancy with IL-21 in regulating B cell survival, proliferation, IgG1 class switching and secretion. Nevertheless, these two cytokines showed distinct functions. IL-21 decreased the expression of CD23 and CD44 while IL-4 increased their expression on activated B cells. IL-21 but not IL-4 sustained the expression of CD138, a plasma cell marker, at a later phase of the B cell response.Collectively, these data indicate that there are three separable outcomes for IL-21 and/or IL-4-stimulated B cells, apoptosis, growth arrest, or co-stimulation. We favor a model where these cytokines promote B cell maturation during a productive T cell-dependent B cell response while favoring growth arrest and apoptosis for non-specifically or inappropriately activated B cells. Furthermore, their distinctive activities may instruct post-germinal center B cells to enter separate differentiation pathways.</p
