Cutting edge: polyinosinic:polycytidylic acid boosts the generation of memory CD8 T cells through melanoma differentiation-associated protein 5 expressed in stromal cells.
Polyinosinic:polycytidylic acid (poly I:C), a synthetic analog of double-stranded viral RNA, serves as a potent adjuvant for vaccination against soluble proteins, pathogens, and tumors. Poly I:C is sensed by both TLR3 in the endosomes and melanoma differentiation-associated protein 5 (MDA5) in the cytoplasm. Although it is known that TLR3 is required for cross-priming of CD8 T cells specific for viral Ags, the role of MDA5 in inducing CD8 T cell responses is still unclear. In this study, we demonstrate that in mice lacking MDA5, the majority of CD8 T cells do not survive after primary immunization with poly I:C and Ag, impairing memory response to subsequent Ag challenge. Furthermore, bone marrow chimera experiments revealed that MDA5 expression in radiation-resistant stromal cells, but not in radiation-sensitive hematopoietic cells, is essential for establishing CD8 T cell memory. We conclude that MDA5 and TLR3 mediate substantially distinct yet complementary functions during poly I:C-mediated activation of Ag-specific CD8 T cell responses.
Wang
Yaming
Y
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Cella
Marina
M
Gilfillan
Susan
S
Colonna
Marco
M
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology* / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D007156:Immunologic Memory; D000072640:Interferon-Induced Helicase, IFIH1; D008213:Lymphocyte Activation / Q000276:immunology* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011070:Poly I-C / Q000494:pharmacology*; D011828:Radiation Chimera; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D018984:Epitopes, T-Lymphocyte; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C