4.7 Article

Distinct and complementary functions of MDA5 and TLR3 in poly(I:C)-mediated activation of mouse NK cells

Journal

JOURNAL OF EXPERIMENTAL MEDICINE
Volume 206, Issue 13, Pages 2967-2976

Publisher

ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20091181

Keywords

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Funding

  1. Juvenile Diabetes Research Foundation [24-2007-420]
  2. National Heart, Lung, and Blood Institute [F30HL096354]

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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 CD8 alpha 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.

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