Soluble HLA-I-mediated secretion of TGF-β1 by human NK cells and consequent down-regulation of anti-tumor cytolytic activity

Massimo Ghio, Paola Contini, Simone Negrini, Silvia Boero, Alessandra Musso, Alessandro Poggi

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Soluble HLA class I (sHLA-I) molecules can regulate survival of NK cells and their anti-tumor killing activity. Herein, we have analysed whether interaction of sHLA-I with CD8 and/or different isoforms of killer Ig-like receptors (KIR) induced secretion of transforming growth factor (TGF)-β1. CD8+KIR- NK cell clones secreted TGF-β1 upon the interaction of sHLA-I with CD8 molecule. sHLA-Cw4 or sHLA-Cw3 alleles engaging inhibitory isoforms of KIR, namely KIR2DL1 or KIR2DL2, strongly downregulated TGF-β1 production elicited through CD8. On the other hand, sHLA-Cw4 or sHLA-Cw3 alleles induced secretion of TGF-β1 by ligation of stimulatory KIR2DS1 or KIR2DS2 isoforms. TGF-β1 strongly reduced NK cell-mediated tumor cell lysis and production of pro-inflammatory cytokines such as TNF-α and IFN-γ. Also, TGF-β1 inhibited NK cell cytolysis induced by the engagement of stimulatory receptors including NKG2D, DNAM1, 2B4, CD69, NKp30, NKp44 and NKp46. The IL-2-dependent surface upregulation of some of these receptors was prevented by TGF-β1. Furthermore, TGF-β1 hampered IL-2-induced NK cell proliferation but not IL-2-mediated rescue from apoptosis of NK cells. Depletion of TGF-β1 restored all the NK cell-mediated functional activities analysed. Taken together these findings suggest that sHLA-I antigens may downregulate the NK cell-mediated innate response by inducing TGF-β1 release.

Original languageEnglish
Pages (from-to)3459-3468
Number of pages10
JournalEuropean Journal of Immunology
Volume39
Issue number12
DOIs
Publication statusPublished - Dec 2009

Fingerprint

Transforming Growth Factors
Natural Killer Cells
Down-Regulation
Neoplasms
Interleukin-2
Protein Isoforms
KIR2DL2 Receptor
KIR2DL1 Receptors
NK Cell Lectin-Like Receptor Subfamily K
Alleles
Natural Killer Cell Receptors
Histocompatibility Antigens Class I
HLA Antigens
Ligation
Up-Regulation
Clone Cells
Cell Proliferation
Apoptosis
Cytokines

Keywords

  • Cytolysis
  • NK cells
  • Soluble HLA-I
  • TGF-β1

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Soluble HLA-I-mediated secretion of TGF-β1 by human NK cells and consequent down-regulation of anti-tumor cytolytic activity. / Ghio, Massimo; Contini, Paola; Negrini, Simone; Boero, Silvia; Musso, Alessandra; Poggi, Alessandro.

In: European Journal of Immunology, Vol. 39, No. 12, 12.2009, p. 3459-3468.

Research output: Contribution to journalArticle

Ghio, Massimo ; Contini, Paola ; Negrini, Simone ; Boero, Silvia ; Musso, Alessandra ; Poggi, Alessandro. / Soluble HLA-I-mediated secretion of TGF-β1 by human NK cells and consequent down-regulation of anti-tumor cytolytic activity. In: European Journal of Immunology. 2009 ; Vol. 39, No. 12. pp. 3459-3468.
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AU - Musso, Alessandra

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