IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis

Kesley Attridge, Chun Jing Wang, Lukasz Wardzinski, Rupert Kenefeck, Jayne L. Chamberlain, Claire Manzotti, Manfred Kopf, Lucy S.K. Walker

Research output: Contribution to journalArticlepeer-review


Modulation of regulatory T cell (Treg) suppression has important implications for vaccine development, the effectiveness of tumor surveillance, and the emergence of autoimmunity. We have previously shown that the cytokine IL-21 can counteract Treg suppression. However, whether this reflects an effect of IL-21 on Treg, conventional T cells, or antigen-presenting cells is not known. Here we have used lymphocyte populations from IL-21R-deficient mice to pinpoint which cell type needs to be targeted by IL-21 for Treg suppression to be overcome. We show that IL-21 counteracts suppression by acting on conventional T cells and that this is associated with inhibition of IL-2 production. Despite the lack of IL-2, conventional T-cell responses proceed unimpaired because IL-21 can substitute for IL-2 as a T cell growth factor. However, IL-21 is unable to substitute for IL-2 in supporting the Treg compartment. Thus, IL-21 signaling in conventional T cells indirectly impacts Treg homeostasis by decreasing IL-2 availability. These data demonstrate that IL-21 and IL-2 can have overlapping roles in promoting conventional T-cell responses but play distinct roles in controlling Treg homeostasis and function. The data also suggest a new paradigm whereby cytokines can promote immunity by inhibiting IL-2.

Original languageEnglish
Pages (from-to)4656-4664
Number of pages9
Issue number20
Publication statusPublished - 17 May 2012


  • receptors
  • cell proliferation
  • cell survival
  • cultured cells
  • down-regulation
  • homeostasis
  • interleukin-2
  • interleukin-21 receptor alpha subunit
  • interleukins
  • Lymphocyte activation
  • antigen
  • T-cell
  • T-lymphocytes
  • regulatory T-lymphocytes


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