Interleukin‐2 is essential for CD4+CD25+ regulatory T cell function

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Abstract
Constitutive expression of CD25, the IL‐2 receptor α‐chain, defines a distinct population of CD4+ T cells (Treg) with suppressive activity in vitro and in vivo. IL‐2 has been implicated in the generation and maintenance of Treg, however, a functional contribution of the IL‐2 receptor during suppression is thus far unknown. We show that IL‐2 is required for Treg function in vitro, since suppression is completely abrogated by selective blocking of the IL‐2 receptor on Treg during co‐culture with responder T cells. We demonstrate that Treg, which do not produce IL‐2, compete for IL‐2 secreted by responder T cells. In accordance with the idea of competition being part of the suppressive mechanism, in vitro neutralization of IL‐2 mimics all effects of Treg. Conversely, recombinant IL‐2 abrogates inhibition of IL‐2 production in responder T cells, the hallmark of Treg suppression. Finally, activation in the presence of IL‐2 primes Treg to produce IL‐10 upon secondary stimulation, indicating that IL‐2 uptake is also required to induce additional suppressive factors that might be more relevant for suppression in vivo. We propose the parakrine uptake of soluble mediators as a flexible mechanism to adapt Treg activity to the strength of the responder T cell reaction.