Targeting poly(I:C) to the TLR3-independent pathway boosts effector CD8 T cell differentiation through IFN-alpha/beta.
Poly(I:C) is an adjuvant used for antitumor treatment and vaccines because of its prominent effects on CD8 T cells and NK cells. Poly(I:C) binds TLR3 and this interaction is thought to be central for driving cell-mediated immune responses. We investigated the importance of TLR3 in poly(I:C)-mediated endogenous CD8 T cell responses using the pathogenic T cell stimulant Staphylococcus aureus enterotoxin A. While the responsive CD8 T cells expanded comparably in both wild-type and TLR3(-/-) mice, differentiation of effector CD8 T cells was enhanced by poly(I:C) in the TLR3(-/-) mice. A higher percentage of Ag-specific CD8 T cells became IFN-gamma and TNF-alpha producers in the absence of TLR3 signaling. Consistent with this boosted response was the observation that TLR3-deficient cells synthesized less IL-10 compared with TLR3-sufficient cells in response to poly(I:C). Ultimately, however, the fundamental mechanism of CD8 effector T cell differentiation through the TLR3-independent pathway was shown to be completely IFN-alpha/beta-dependent. Administration of IFN-alpha/beta-neutralizing Abs abolished the poly(I:C) effects in TLR3(-/-) mice. These findings reveal specific roles of how dsRNA receptors shape CD8 T cell responses, which should be considered as poly(I:C) is authenticated as a therapeutic adjuvant used in vaccines.
Ngoi
Soo M
SM
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Tovey
Michael G
MG
Vella
Anthony T
AT
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D004768:Enterotoxins / Q000276:immunology / Q000494:pharmacology; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology*; D012330:RNA, Double-Stranded / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D000906:Antibodies; D019496:Cancer Vaccines; D004768:Enterotoxins; D016898:Interferon-alpha; D012330:RNA, Double-Stranded; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C026066:enterotoxin A, Staphylococcal; D016899:Interferon-beta; D007371:Interferon-gamma; D011070:Poly I-C