Methods and compositions for modulating interleukin-21 (IL-21)/IL-21 receptor (MU-1) activity using agonists or antagonists of IL-21 or IL-21 receptor ("IL-21R" or "MU-1"), are disclosed. IL-21/IL-21R antagonists can be used to induce immune suppression in vivo, e.g., for treating or preventing immune cell-associated pathologies (e.g., pathologies associated with aberrant activity of one or more of mature T cells (mature CD8+, mature CD4+ T cells), mature NK cells, B cells, macrophages and megakaryocytes, including transplant rejection and autoimmune disorders). IL-21/IL-21R agonists can be used by themselves or in combination with an antigen, e.g., as an adjuvant (e.g., a vaccine adjuvant), to up-regulate an immune response in vivo, e.g., for example, for use in treating cancer and infectious disorders.