IFNα signaling through PKC-θ is essential for antitumor NK cell function
Résumé
We have previously shown that the development of a major histocompatibility complex class I (MHC-I)-deficient tumor was favored in protein kinase C-θ knockout (PKC-θ-/-) mice compared to that occurring in wild-type mice. This phenomenon was associated with scarce recruitment of natural killer (NK) cells to the tumor site, as well as impaired NK cell activation and reduced cytotoxicity ex vivo. Poly-inosinic:cytidylic acid (poly I:C) treatment activated PKC-θ in NK cells depending on the presence of a soluble factor produced by a different splenocyte subset. In the present work, we sought to analyze whether interleukin-15 (IL-15) and/or interferon-α (IFNα) mediate PKC-θ-dependent antitumor NK cell function. We found that IL-15 improves NK cell viability, granzyme B expression, degranulation capacity and interferon-γ (IFNγ) secretion independently of PKC-θ. In contrast, we found that IFNα improves the degranulation capability of NK cells against target cancer cells in a PKC-θ-dependent fashion both ex vivo and in vivo. Furthermore, IFNα induces PKC-θ auto-phosphorylation in NK cells, in a signal transduction pathway involving both phosphatidylinositol-3-kinase (PI3K) and phospholipase-C (PLC) activation. PKC-θ dependence was further implicated in IFNα-induced transcriptional upregulation of chemokine (C-X-C motif) ligand 10 (CXCL10), a signal transducer and activator of transcription-1 (STAT-1)-dependent target of IFNα. The absence of PKC-θ did not affect IFNα-induced STAT-1 Tyr701 phosphorylation but affected the increase in STAT-1 phosphorylation on Ser727, attenuating CXCL10 secretion. This connection between IFNα and PKC-θ in NK cells may be exploited in NK cell-based tumor immunotherapy.
Mots clés
CDK8
cyclin-dependent kinase 8
CXCL10
(C-X-C motif) ligand 10/CXCL10
FCS
fetal calf serum
IFN-α
IL-15
IFNA1
IFNα
interferon-α
IFNγ
interferon-γ
IFNG
interleukin-15/IL15
MACS
magnetic cell separation
MEF
murine embryonic fibroblast
MHC-I
major histocompability complex class I/MHC-I
NK cells
NK
natural killer
PI3K
phosphatidylinositol-3-kinase
PKC-θ
protein kinase C-θ
PRKCQ
PLC
phospholipase-C
Poly I:C
poly-inosinic:cytidilic acid
RT-PCR
real-time polymerase chain reaction
STAT-1
signal transducer and activator of transcription-1/STAT1.
Domaines
Sciences du Vivant [q-bio]
Fichier principal
IRMB 7_p31_IFNα signaling through PKC-θ is essential for antitumor NK cell function-koni-03-e948705.pdf (582.38 Ko)
Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte