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

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.

Author information

1
INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France;
2
Department of Head and Neck Surgery, University Hospital of Besançon, 25000 Besançon, France;
3
INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; Clinical Investigation Center for Biotherapies, 25000 Besançon, France;
4
INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; Etablissement Français du Sang, 25000 Besançon, France;
5
INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; INSERM Unit 1007, University of Paris Descartes, 75270 Paris, France;
6
INSERM Unit 1007, University of Paris Descartes, 75270 Paris, France;
7
INSERM Unit 1015, Gustave Roussy Cancer Campus, 94805 Villejuif, France;
8
INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; Clinical Investigation Center for Biotherapies, 25000 Besançon, France; Department of Medical Oncology, University Hospital of Besançon, 25000 Besançon, France; and.
9
Ludwig Center for Cancer Research of the University of Lausanne, Lausanne 1066, Switzerland.
10
INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; Clinical Investigation Center for Biotherapies, 25000 Besançon, France; Etablissement Français du Sang, 25000 Besançon, France; Department of Medical Oncology, University Hospital of Besançon, 25000 Besançon, France; and christophe.borg@efs.sante.fr.

Abstract

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.

PMID:
27233967
DOI:
10.4049/jimmunol.1501147
[Indexed for MEDLINE]
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