IL-21-Induced MHC Class II+ NK Cells Promote the Expansion of Human Uncommitted CD4+ Central Memory T Cells in a Macrophage Migration Inhibitory Factor-Dependent Manner

J Immunol. 2016 Jul 1;197(1):85-96. doi: 10.4049/jimmunol.1501147. Epub 2016 May 27.


NK cells are critical for innate immunity-mediated protection. The main roles of NK cells rely on their cytotoxic functions or depend on the tuning of Th1 adaptive immunity by IFN-γ. However, the precise influence of inflammatory cytokines on NK cell and CD4 T lymphocyte interactions was never investigated. In this study, we provide evidence that IL-21, a cytokine produced during chronic inflammation or infectious diseases, promotes the differentiation of a specific subset of NK cells coexpressing CD86 and HLA-DR and lacking NKp44. More importantly, IL-21-propagated HLA-DR(+) NK cells produce macrophage migration inhibitory factor and provide costimulatory signaling during naive CD4(+) T cell priming inducing the differentiation of uncommitted central memory T cells. Central memory T cells expanded in the presence of HLA-DR(+) NK cells are CXCR3(+)CCR6(-)CCR4(-)CXCR5(-) and produce IL-2, as well as low levels of TNF-α. Costimulation of CD4(+) T cells by HLA-DR(+) NK cells prevents the acquisition of effector memory phenotype induced by IL-2. Moreover, we identified this population of NK HLA-DR(+) macrophage migration inhibitory factor(+) cells in inflammatory human appendix. Collectively, these results demonstrate a novel function for IL-21 in tuning NK and CD4(+) T cell interactions promoting a specific expansion of central memory lymphocytes.

MeSH terms

  • B7-2 Antigen / metabolism
  • Cell Communication
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic
  • HLA-DR Antigens / metabolism
  • Humans
  • Immunity, Innate
  • Immunologic Memory
  • Inflammation / immunology*
  • Interleukins / metabolism*
  • Intramolecular Oxidoreductases / metabolism*
  • Killer Cells, Natural / immunology*
  • Macrophage Migration-Inhibitory Factors / metabolism*
  • Macrophages / immunology*
  • Th1 Cells / immunology*
  • Tonsillitis / immunology*


  • B7-2 Antigen
  • Cytokines
  • HLA-DR Antigens
  • Interleukins
  • Macrophage Migration-Inhibitory Factors
  • Intramolecular Oxidoreductases
  • MIF protein, human
  • interleukin-21