Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines.
Toll-like receptors (TLRs) may need to cooperate with each other to be effective in detecting imminent infection and trigger immune responses. Understanding is still limited about the intracellular mechanism of this cooperation. We found that when certain TLRs are involved, dendritic cells (DCs) establish unidirectional intracellular cross-talk, in which the MyD88-independent TRIF-dependent pathway amplifies the MyD88-dependent DC function through a JNK-dependent mechanism. The amplified MyD88-dependent DC function determines the induction of the T cell response to a given vaccine in vivo. Therefore, our study revealed an underlying TLR mechanism governing the functional, nonrandom interplay among TLRs for recognition of combinatorial ligands that may be dangerous to the host, providing important guidance for design of novel synergistic molecular vaccine adjuvants.
Zhu
Qing
Q
Vaccine Branch, Center for Cancer Research, and Laboratory of Experimental Immunology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Egelston
Colt
C
Vivekanandhan
Aravindhan
A
Uematsu
Satoshi
S
Akira
Shizuo
S
Klinman
Dennis M
DM
Belyakov
Igor M
IM
Berzofsky
Jay A
JA
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014612:Vaccines / Q000276:immunology*
D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D014612:Vaccines