Cell type IL-21 actions References Th17 cells IL-21 is an autocrine cytokine for Th17 differentiation and up-regulates IL-23R expression to maintain Th17 cell phenotype [20,28,29] TFH  cells Facilitates TFH differentiation; IL-21 is a major effector cytokine of TFH [30-32] Th1, Th2 cells Inhibits IFN-γ but increases other Th1 molecules; IL-21 can be produced by Th1 and Th2 cells [2] Treg cells Counteracts Treg suppression by acting on conventional T cells [62] CD8 T cells Up-regulates proliferation and effector function; Sustains effector function during antigen persistence [2-5] B cells Promotes B cell proliferation, plasma cell differentiation, IgG production, GC formation; Inhibits IgE production by inducing apoptosis of IgE-expressing B cells [35-39] DCs IL-21R is required for antigen transport by DCs [63] NKT cells Enhances survival, proliferation, granzyme B expression, cytokine production; NKT cells also produce IL-21 [12,13] Murine model     Infection Controls chronic viral infection by sustaining CD8 T cell function [3-5] SLE Mice with SLE produce high levels of IL-21; IL-21R deficiency or IL-21R.Fc treatment inhibits B cell-mediated lupus pathology [18,40,41] T1D IL-21 over-expression in pancreatic β cells induces T1D in C57Bl/6 mice; IL-21 or IL-21R deficiency prevents T1D onset in NOD mice; IL-21R.Fc treatment prolongs islet graft survival; CCR9+ Th cells in the pancreas produce IL-21; IL-21 signal controls DC-mediated antigen transport [6,7,9,34,63] IBD IL-21 deficient mice are protected against colitis  [64] RA IL-21R deficient K/BxN mice inhibited the development of arthritis [65] EAE IL-21 or IL-21R deficiency does not prevent MOG-induced EAE [43,44] Tumor IL-21 monotherapy inhibits tumor growth in various models [66] Human disease     Autoimmunity Polymorphisms in IL-21 or IL-21R genes associate with SLE, T1D, IBD, and RA; Elevated expression of IL-21 or IL-21R was found in patients with SLE, IBD, and RA   [66-69] Tumor Recombinant IL-21 is undergoing Phase I and II testing for treatment of metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma [70] DCs: Dendritic Cells; EAE: Experimental Autoimmune Encephalomyelitis; GC: Germinal Center; IBD: Inflammatory Bowel Disease; MOG: Myelin Oligodendrocyte Glycoprotein; NKT: Natural Killer T; NOD: Non-Obese Diabetic; RA: Rheumatoid Arthritis; SLE: Systemic Lupus Erythematosus; T1D: Type 1 Diabetes; TFH: Follicular Helper T; Th: T Helper; Treg: Regulatory T

Table 1: Immunoregulatory effects of IL-21 on various cell types and immune responses.