IL‐1β inhibits ILC3 while favoring NK‐cell maturation of umbilical cord blood CD34⁺ precursors

Abstract

NK cells are innate lymphocytes characterized by the expression of nuclear factor interleukin 3 regulated (NFIL3 or E4BP4), eomesodermin (EOMES) transcription factors (TFs), and by the ability to exert cytolytic activity and release IFN-γ. In the haploidenticalhematopoietic stem cell transplantation (haplo-HSCT) setting, CD34 + donor derived NK cells play a major role in the control of leukemic relapses. Therefore, it is important to better define cytokines that influence NK-cell differentiation from CD34 + precursors. We analyzed the effects of IL-1β on NK-cell differentiation from umbilical cord blood (UCB) CD34 + cells. While IL-1β inhibited CD161 + CD56 + cell proliferation, an increased expression of LFA-1, CD94/NKG2A, KIRs, and perforin on CD56 + cells was detected. In addition, within the CD161 + CD56 + IL-1RI + LFA-1 − cell fraction (representing group 3 innate lymphoid cells, ILC3-like cells), a significant increase of EOMES, NKp46, and CD94/NKG2A receptors, cytolytic granules, and IFN-γ was detected. This increase was paralleled by a decrease of related orphan receptors (RORγt) TF, NKp44 expression, and IL-22 production. These data suggest that IL-1β inhibits ILC3-while favoring NK-cell maturation. Since in haplo-HSCT conditioning regimen, infections or residual leukemia cells may induce IL-1β production, this may influence the NK/ILC3 development from donor-derived CD34 + precursors.Keywords: IL-1β r ILC3 r Innate immunity r NK cells r NK-cell development Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNatural killer (NK) cells are major effectors of the innate immunity. They are able to rapidly eliminate virally infected cells or tumor cells [1][2][3]. Their activity is finely regulated by a number of activating and inhibitory receptors that tune their cytolytic Correspondence: Dr. Chiara Vitale e-mail: chiara.vitale@unige.it activity and cytokine secretion [4,5]. The main activating receptors include NKp46, NKp30, and NKp44 (collectively termed natural cytotoxicity receptors), NKG2D, and DNAM-1 [6,7]. In addition, NK cells express inhibitory receptors specific for HLA class I molecules, including killer immunoglobulin-like(Ig-like) receptors (KIRs), specific for allotypic HLA class I determinants, and * These authors contributed equally to this work as senior co-authors. Eur. J. Immunol. 2015Immunol. . 45: 2061Immunol. -2071 CD94/NKG2A specific for 9]. NK cells are characterized by production of IFN-γ and the expression of cytolytic granules. Their development requires the expression of E4BP4 (NFIL3, nuclear factor interleukin 3), Tbx21 (T-bet), eomesodermin (EOMES) transcription factor (TF) [10][11][12][13][14] and occurs primarily in the BM, proceeding through a multistep process characterized by the sequential acquisition of markers/receptors (including CD117, CD161, CD56, CD94/NKG2A, LFA-1, CD16, and KIRs) and functions [10,11,15]. NK cells are developmentally related to innate lymphoid cells (ILCs) as they derive fro...

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