IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Engagement of TLR3, TLR7 and NKG2D regulate IFN-gamma secretion but not NKG2D-mediated cytotoxicity by human NK cells stimulated with bsuboptimal doses of IL-12
Autor/es:
MARÍA VICTORIA GIRART; MERCEDES BEATRIZ FUERTES; CAROLINA INES DOMAICA; LUCAS EZEQUIEL ROSSI; NORBERTO WALTER ZWIRNER
Revista:
JOURNAL OF IMMUNOLOGY
Editorial:
The American Association of Immunology
Referencias:
Lugar: Bethesda; Año: 2007
ISSN:
0022-1767
Resumen:
NK cells express different TLRs such as TLR3, TLR7 and TLR9, but little is known about their role in NK cell stimulation. In this work, we used specific agonists (polyI:C, loxoribine and ODNs) to stimulate human NK cells without or with suboptimal doses of IL-12, IL-15 or IFN-g, and investigated the secretion of IFN-g, cytotoxicity and expression of the activating receptor NKG2D. PolyI:C and loxoribine, in conjunction with IL-12 but not IL-15, triggered secretion of IFN-g. Inhibition of IFN-g secretion by chloroquine suggested that internalization of the TLR agonists was necessary. Also, secretion of IFN-g was dependent on MEK1/ERK, p38 MAPK, p70S6 kinase and NF-kB but not on calcineurin. IFN-g induced a similar effect but promoted lesser IFN-g secretion. However, cytotoxicity (51Cr release assays) against MICA- and MICA+ tumor targets remained unchanged as well as the expression of the NKG2D receptor. Excitingly, IFN-g secretion was significantly increased when NK cells were stimulated with polyI:C or loxoribine and IL-12, and NKG2D engagement was induced by coculture with MICA+ tumor cells in a PI3K-dependent manner. We conclude that resting NK cells secrete high levels of IFN-g in response to agonists of TLR3 or TLR7 and IL-12, and this effect can be further enhanced by co-stimulation through NKG2D. Hence, integration of the signaling cascades that involve TLR3, TLR7, IL-12 and NKG2D emerges as a critical step to promote IFN-g- dependent NK cell-mediated effector functions which could be a strategy to promote Th1- biased immune responses in pathological situations such as cancer.