Functional Plasticity of Dendritic Cell Subsets as Mediated by CD40 Versus B7 Activation

Abstract

Murine dendritic cells (DCs) can present Ag in an immunogenic or tolerogenic fashion, the distinction depending on either the occurrence of specialized DC subsets or the maturation or activation state of the DC. Although DC subsets may be programmed to direct either tolerance or immunity, it is not known whether appropriate environmental stimulation can result in complete flexibility of a basic program. Using splenic CD8− and CD8+ DCs that mediate the respective immunogenic and tolerogenic presentation of self peptides, we show that both the in vivo and in vitro activities of either subset can be altered by ligation of specific surface receptors. Otherwise immunogenic CD8− DCs become tolerogenic upon B7 ligation by soluble CTLA-4, a maneuver that initiates immunosuppressive tryptophan catabolism. In contrast, CD40 ligation on tolerogenic CD8+ DCs makes these cells capable of immunogenic presentation. Thus, environmental conditioning by T cell ligands may alter the default function of DC subsets to meet the needs of flexibility and redundancy.

Distinct roles of immunoreceptor tyrosine‐based motifs in immunosuppressive indoleamine 2,3‐dioxygenase 1

“…We sensitized female mice with the H‐2D b –restricted HY peptide presented by a combination of immunogenic cDCs and a minority fraction of transfected Ido1 −/− pDCs. Two weeks later, we evaluated reactivity to intrafootpad challenge with the HY antigen, according to an established protocol for measuring the induction of immunoreactivity versus tolerance 22, 26, 31, 32, 33. As expected, overexpression of WT IDO1 elicited an immunosuppressive phenotype in Ido1 −/− pDCs, such that antigen sensitization by the otherwise immunogenic DCs was negated 13.…”

High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9–TRIF pathway

“…Flexibility in DC presentation programs mostly reflects autocrine effects by a set of cytokines, which either reinforce or subvert a default presentation profile 14 . Typically, the IL-12-IL-23 pair 15 and IL-6 16 induce immunogenic presentation, whereas TGF-b 17 and type I or type II interferons (IFNs) 18 promote tolerance, via transcriptional 19 or posttranslational 20 regulation of IDO1.…”

A GpC-Rich Oligonucleotide Acts on Plasmacytoid Dendritic Cells To Promote Immune Suppression

“…Mice homozygous for the TLR7 (Tlr7 2/2 ) mutation were obtained from The Jackson Laboratory. The HY peptide (amino acid sequence, WMHHNMDLI) was synthesized and purified as described (25). Endotoxin-free GpC-ODN 1826 (59-TCCATGAGCTTCCTAAGCTT-39) and the negative control thereof (59-TCCATGAATTTCCTAAATTT-39), both on a phosphorothioate backbone, were purchased from Invitrogen Life Technologies.…”