TY - JOUR
T1 - The adjuvant effects of the toll-like receptor 3 ligand polyinosinic-cytidylic acid poly (I:C) on antigen-specific CD8+ T cell responses are partially dependent on NK cells with the induction of a beneficial cytokine milieu
AU - Salem, Mohamed L.
AU - EL-Naggar, Sabry A.
AU - Kadima, Andre
AU - Gillanders, William E.
AU - Cole, David J.
N1 - Funding Information:
This work was supported by the National Institutes of Health Grant 1 R01 CA94856-01.
PY - 2006/6/12
Y1 - 2006/6/12
N2 - Poly (I:C), a TLR3 ligand, has shown promise as a vaccine adjuvant to CD8+ T cell responses. The underlying mechanisms involved in creating this adjuvant response in vivo, however, have not been well defined. In this study, we explored the contribution of NK cells and inflammatory cytokines in mediation the poly (I:C) adjuvant effects. Enhanced antigen-specific CD8+ T cell responses were observed only when poly (I:C) was administered within 4 h of peptide vaccination. Poly (I:C) treatment was associated with a rapid induction of inflammatory cytokines in the serum, including IL-6, IL-10, MCP-1, TNF-α, IFN-α, and IFN-γ, and selective increases in the numbers of NK (NK1.1+CD11b+) cells and Mφ{symbol} (NK1.1-CD11b+), but not NK T (CD3+NK1.1+) cells. NK cells were required for the adjuvant effects of poly (I:C). Poly (I:C) treatment in TNF-α, type I IFNR, IFN-γ, IL-6, IL-12Rβ2, or IL-15 gene-deficient mice revealed a reciprocal interaction and interdependence in the induction of these cytokines, where the absence of one cytokine impacted on the production of others. Further, the adjuvant effects of poly (I:C) were dependent on the endogenous levels of type I IFNs, TNF-α, IFN-γ, IL-12, and IL-15. IFN-α and IFN-β, but not TNF-α or IL-6, were able to mimic the adjuvant effects of poly (I:C). We conclude that the adjuvant effects of poly (I:C) on antigen-specific CD8+ T cells appeared to be exquisitely dependent on the rapid induction of certain beneficial cytokines produced in part by NK cells.
AB - Poly (I:C), a TLR3 ligand, has shown promise as a vaccine adjuvant to CD8+ T cell responses. The underlying mechanisms involved in creating this adjuvant response in vivo, however, have not been well defined. In this study, we explored the contribution of NK cells and inflammatory cytokines in mediation the poly (I:C) adjuvant effects. Enhanced antigen-specific CD8+ T cell responses were observed only when poly (I:C) was administered within 4 h of peptide vaccination. Poly (I:C) treatment was associated with a rapid induction of inflammatory cytokines in the serum, including IL-6, IL-10, MCP-1, TNF-α, IFN-α, and IFN-γ, and selective increases in the numbers of NK (NK1.1+CD11b+) cells and Mφ{symbol} (NK1.1-CD11b+), but not NK T (CD3+NK1.1+) cells. NK cells were required for the adjuvant effects of poly (I:C). Poly (I:C) treatment in TNF-α, type I IFNR, IFN-γ, IL-6, IL-12Rβ2, or IL-15 gene-deficient mice revealed a reciprocal interaction and interdependence in the induction of these cytokines, where the absence of one cytokine impacted on the production of others. Further, the adjuvant effects of poly (I:C) were dependent on the endogenous levels of type I IFNs, TNF-α, IFN-γ, IL-12, and IL-15. IFN-α and IFN-β, but not TNF-α or IL-6, were able to mimic the adjuvant effects of poly (I:C). We conclude that the adjuvant effects of poly (I:C) on antigen-specific CD8+ T cells appeared to be exquisitely dependent on the rapid induction of certain beneficial cytokines produced in part by NK cells.
KW - CD8+ T cells
KW - Cytokines
KW - Dendritic cells
KW - Double-stranded RNA
KW - IFN
KW - MΦ
KW - NK cells
KW - OT-1 cells
KW - OVA
KW - Poly (I:C)
KW - TLR3
KW - Vaccination
UR - http://www.scopus.com/inward/record.url?scp=33744521498&partnerID=8YFLogxK
U2 - 10.1016/j.vaccine.2006.04.010
DO - 10.1016/j.vaccine.2006.04.010
M3 - Article
C2 - 16704888
AN - SCOPUS:33744521498
SN - 0264-410X
VL - 24
SP - 5119
EP - 5132
JO - Vaccine
JF - Vaccine
IS - 24
ER -