IL-21 is an immune activator that also mediates suppression via IL-10

Interleukin-21 (IL-21) is a pleiotropic type I cytokine that is produced predominantly by CD4(+) T cells and natural killer T (NKT) cells. Although IL-21 production is relatively restricted to these two populations of immune cells, its targets are numerous, including multiple lympho-hematopoietic as well as non-hematopoietic lineages. The effects of IL-21 are specific not only to the target cell type, but also depend on the developmental stage of the target cell as well as the available co-stimulatory signals. Accordingly, IL-21 functions not only as a strong inducer of differentiation and proliferation but also as a pro-apoptotic factor. Although most of the effects of IL-21 are immunostimulatory, it has become clear that one of the cytokines that is potently induced by IL-21 in a number of lymphoid lineages is interleukin-10 (IL-10), one of the most immunosuppressive cytokines. The seemingly contradictory actions of IL-21 and IL-10 and the consequences of their co-expression are currently being explored in numerous infectious models, autoimmune diseases, and tumor responses. This review seeks to critically evaluate the evidence concerning the regulation of IL-10 by IL-21 in a number of lineage subsets as well as to discuss the potential positive versus deleterious roles that this co-expression may play in a range of disease models.