Presensitizing with a Toll-like receptor 3 ligand impairs CD8 T-cell effector differentiation and IL-33 responsiveness.
The synthetic double-stranded RNA poly(I:C) is commonly used as an adjuvant to boost CD8 T-cell function; however, polyinosinic:polycytidylic acid [poly(I:C)] can also suppress autoimmune disease. The mechanism by which a single adjuvant achieves two distinct immunoregulatory roles is unknown. Although it is clear that coadministration of poly(I:C) with antigen elicits strong adjuvant effects in mice, we found that poly(I:C) injection before antigen substantially reduced antigen-dependent CD8 T-cell responses. Notably, CD8 T cells sensitized in poly(I:C)-pretreated mice failed to fully up-regulate IL-33R (ST2), which led to impaired T-cell receptor-independent responses to IL-33. In contrast, nonsensitized effector CD8 T cells responded robustly to IL-33 using a two-signal cytokine mechanism. During an acute lung response to Staphylococcus aureus enterotoxin, peripheral injection of poly(I:C) manifested a suppressive process by inhibiting the differentiation of both antigen- and IL-33-responsive CD8 effectors systemically. These findings highlight that early exposure to double-stranded RNA reverses its role as an adjuvant and, importantly, prevents IL-33R up-regulation on CD8 effector T cells to dampen inflammation.
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Soo Mun
SM
Ngoi
Marie-Clare
MC
St Rose
Antoine M
AM
Menoret
Dirk E
DE
Smith
Michael G
MG
Tovey
Adam J
AJ
Adler
Anthony T
AT
Vella
D000818:Animals; D000941:Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology*; D000067596:Interleukin-33; D007378:Interleukins / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D012330:RNA, Double-Stranded / Q000008:administration & dosage; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
D000941:Antigens; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D008024:Ligands; D012330:RNA, Double-Stranded; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3