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: Stephen McCartney, William Vermi, Susan Gilfillan, Marina Cella, Theresa L Murphy, Robert D Schreiber, Kenneth M Murphy, Marco Colonna
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 206 Issue 13 Pg. 2967-76 (Dec 21 2009) ISSN: 1540-9538 [Electronic] United States
• PMID: 19995959 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antigens, Differentiation, T-Lymphocyte
• CD69 antigen
• Cytokines
• Lectins, C-Type
• TLR3 protein, mouse
• Toll-Like Receptor 3
• Interferon-gamma
• Ifih1 protein, mouse
• DEAD-box RNA Helicases
• Interferon-Induced Helicase, IFIH1
• Poly I-C

Topics

• Animals
• Antigens, CD (analysis)
• Antigens, Differentiation, T-Lymphocyte (analysis)
• Coculture Techniques
• Cytokines (blood)
• DEAD-box RNA Helicases (physiology)
• Dendritic Cells (physiology)
• Female
• Interferon-Induced Helicase, IFIH1
• Interferon-gamma (biosynthesis)
• Killer Cells, Natural (drug effects, immunology)
• Lectins, C-Type
• Lymphocyte Activation (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Poly I-C (pharmacology)
• Toll-Like Receptor 3 (physiology)