Abstract
Toll-like receptor (TLR) ligation is believed to skew T cell responses toward T helper (Th)1 differentiation by inducing interleukin (IL)-12 secretion by CD8+ dendritic cells (DCs). However, TLR-dependent Th1 responses occur in the absence of IL-12. To determine how DCs induce Th1 differentiation in the absence of IL-12, we examined the response of IL-12–deficient DCs to bacterial lipopolysaccharide (LPS). We find that LPS activates MyD88-dependent Delta 4 Notch-like ligand expression by CD8− DCs, and that these cells direct Th1 differentiation by an IL-12–independent and Notch-dependent mechanism in vitro and in vivo. Thus, activation of the two DC subsets by TLR4 leads to Th1 responses by two distinct MyD88-dependent pathways.
Highlights
Pathogen eradication requires synergy between the innate and adaptive immune response
Other pathways that have been implicated in directing Th1 differentiation include direct cell–cell signaling through Notch [14,15,16]
We report that LPS induces MyD88-dependent expression of IL-12 by CD8+ DCs, it induces Delta 4 on spleen CD8− DCs, and that the latter leads to IL-12–independent Th1 differentiation in vivo
Summary
CD8− DCs induce IL-12–independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS. Toll-like receptor (TLR) ligation is believed to skew T cell responses toward T helper (Th) differentiation by inducing interleukin (IL)-12 secretion by CD8+ dendritic cells (DCs). TLR-dependent Th1 responses occur in the absence of IL-12. To determine how DCs induce Th1 differentiation in the absence of IL-12, we examined the response of IL-12–deficient DCs to bacterial lipopolysaccharide (LPS). We find that LPS activates MyD88dependent Delta 4 Notch-like ligand expression by CD8− DCs, and that these cells direct Th1 differentiation by an IL-12–independent and Notch-dependent mechanism in vitro and in vivo. Activation of the two DC subsets by TLR4 leads to Th1 responses by two distinct MyD88-dependent pathways
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