title: Distinct and complementary functions of MDA5 and TLR3 in poly(I:C)-mediated activation of mouse NK cells.
abstract: The double-stranded RNA (dsRNA) analogue poly(I:C) is a promising adjuvant for cancer vaccines because it activates both dendritic cells (DCs) and natural killer (NK) cells, concurrently promoting adaptive and innate anticancer responses. Poly(I:C) acts through two dsRNA sensors, Toll-like receptor 3 (TLR3) and melanoma differentiation-associated protein-5 (MDA5). Here, we investigated the relative contributions of MDA5 and TLR3 to poly(I:C)-mediated NK cell activation using MDA5(-/-), TLR3(-/-), and MDA5(-/-)TLR3(-/-) mice. MDA5 was crucial for NK cell activation, whereas TLR3 had a minor impact most evident in the absence of MDA5. MDA5 and TLR3 activated NK cells indirectly through accessory cells and induced the distinct stimulatory cytokines interferon-alpha and interleukin-12, respectively. To identify the relevant accessory cells in vivo, we generated bone marrow chimeras between either wild-type (WT) and MDA5(-/-) or WT and TLR3(-/-) mice. Interestingly, multiple accessory cells were implicated, with MDA5 acting primarily in stromal cells and TLR3 predominantly in hematopoietic cells. Furthermore, poly(I:C)-mediated NK cell activation was not notably impaired in mice lacking CD8alpha DCs, providing further evidence that poly(I:C) acts through diverse accessory cells rather than solely through DCs. These results demonstrate distinct yet complementary roles for MDA5 and TLR3 in poly(I:C)-mediated NK cell activation.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: McCartney
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.forename: Susan
authors.initials: S
authors.lastname: Gilfillan
authors.forename: Marina
authors.initials: M
authors.lastname: Cella
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Murphy
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D018920:Coculture Techniques; D016207:Cytokines / Q000097:blood; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D000072640:Interferon-Induced Helicase, IFIH1; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000494:pharmacology*; D051196:Toll-Like Receptor 3 / Q000502:physiology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D007371:Interferon-gamma; D037181:Lectins, C-Type; D011070:Poly I-C; D051196:Toll-Like Receptor 3; D000099192:CD69 Antigens; C519703:TLR3 protein, mouse; C510592:Ifih1 protein, mouse