Prostaglandin D2 inhibits the production of IFN-gamma by invariant NK T cells: consequences in the control of B16 melanoma.
Invariant NK T (iNKT) cells are a subset of innate/memory lymphocytes that recognize lipid Ags presented by CD1d-expressing APCs such as dendritic cells (DCs). Upon primary stimulation through their TCR, iNKT cells promptly produce large amounts of IFN-gamma and/or IL-4 that play critical roles in the regulation of innate and adaptive immune responses. To date, the role of environmental factors on iNKT cell functions has been poorly investigated. In this study, we addressed the question of whether PGD2, a potent eicosanoid lipid mediator involved in immune responses and inflammation, could be important in DC/iNKT cell cross-talk. We show that PGD2 dramatically reduced the production of IFN-gamma, but not IL-4, by iNKT cells in response to the superagonist alpha-galactosylceramide (alpha-GalCer) both in vitro and in vivo. This effect is mediated by the D prostanoid receptor 1 (DP1) expressed by DCs and iNKT cells and requires protein kinase A activation. We also report that PGD2 and BW245C (a selective DP1 agonist) reduce the protective effects of alpha-GalCer in B16F10-induced melanoma metastasis, an effect that depends on IFN-gamma production by iNKT cells. As a whole, these data reveal novel pathways regulating iNKT cell biologic functions and confirm the immunoregulatory roles of PGD2 on the innate response.
Torres
David
D
Institut National de la Santé et de la Recherche Médicale, Unité 547, Lille, France.
Paget
Christophe
C
Fontaine
Josette
J
Mallevaey
Thierry
T
Matsuoka
Toshiyuki
T
Maruyama
Takayuki
T
Narumiya
Shuh
S
Capron
Monique
M
Gosset
Philippe
P
Faveeuw
Christelle
C
Trottein
François
F
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D006827:Hydantoins / Q000494:pharmacology; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D008546:Melanoma, Experimental / Q000276:immunology* / Q000556:secondary; D051379:Mice; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D006827:Hydantoins; D011982:Receptors, Prostaglandin; C527097:prostanoid D receptor 1, mouse; C030669:BW 245C; D007371:Interferon-gamma; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015230:Prostaglandin D2