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The homeostasis of CD4 + CD25 +  regulatory T cells (Tregs) depends on the cytokine interleukin (IL)‐2. As IL‐21 shares sequence homology with IL‐2 and the IL‐21 receptors contain a γ‐chain common to IL‐2, we hypothesized that IL‐21 could also affect the homeostasis of Tregs. We tested this hypothesis in experimental autoimmune encephalomyelitis (EAE), an animal model of relapsing‐remitting human multiple sclerosis. We show that blockade of IL‐21 in SJL/J mice before and after the induction of EAE enhances the influx of inflammatory cells into the central nervous system (CNS). The blockade of IL‐21 leads to proliferation of proteolipid peptide (PLP139‐151)‐autoreactive CD4 +  T cells, which are capable to cause severe EAE in adoptively transferred recipient mice. Conversely, Tregs from mice where IL‐21 was blocked, lose their capacity to prevent EAE induced PLP139‐151‐reactive T cells. Notably, direct effects of IL‐21 on Tregs are confirmed by studies of blockade of IL‐21 in mice expressing a green fluorescent protein ‘knocked’ into a Foxp3 allele, in which a reduction of the number of Tregs and a downregulation of their frequency and expression of Foxp3 are observed. These data suggest a role of the IL‐21/IL‐21R axis in the homeostasis of Tregs in CNS autoimmunity.

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