Novel Mechanisms Underlying the Immediate and Transient Global Tolerization of Splenic Dendritic Cells after Vaccination with a Self-Antigen

Abstract

Dendritic cells (DC) are important orchestrators of the immune response, ensuring that immunity against pathogens is generated while immunity against healthy tissues is prevented. Using the tumor Ag MUC1, we previously showed that i.v. immunization of MUC1.Tg mice, but not WT, with a MUC1 peptide resulted in transient tolerization of all splenic DC. These DC did not upregulate costimulatory molecules and induced regulatory T cells (Treg) rather than effector T cells. They were characterized by suppressed expression of a cohort of pancreatic enzymes not previously reported in DC, which were upregulated in DC presenting the same MUC1 peptide as a foreign Ag. Here we examined the self Ag-tolerized DC phenotype, function and mechanisms responsible for inducing or maintaining their tolerized state. Tolerized DC share some characteristics with immature DC (iDC), such as a less inflammatory cytokine/chemokine profile, deficient activation of NFκB, and sustained expression of zDC and CCR2. However, tolerized DC demonstrated a novel inducible expression of Aldh1/2 and phospho-STAT3. Suppressed expression of one of the pancreatic enzymes, trypsin, in these DC impedes their ability to degrade extracellular matrix thus affecting their motility. Suppressed metallopeptidases, reflected in low expression of CPB1, prevent optimal Ag-specific CD4+ T cell proliferation suggesting their role in Ag processing. Tolerized DC were not refractory to maturation after stimulation with a TLR3 agonist, illustrating that this tolerized state is not terminally differentiated and that tolerized DC can recover their ability to induce immunity to foreign Ags.

Targeting of anti-citrullinated protein/peptide antibodies in rheumatoid arthritis using peptides mimicking endogenously citrullinated fibrinogen antigens

“…Farkas et al . demonstrated that mucin 1 transgenic mice developed transient tolerization of splenic dendritic cells when intravenously immunized with a mucin 1 peptide [ 30 , 31 ]. In systemic lupus erythematosus (SLE), antigen-induced tolerance has been widely addressed.…”

Fifty Shades of Transplantation Tolerance: Beyond a Binary Tolerant/Non-Tolerant Paradigm

“…Dendritic cell maturation has been shown to be impaired upon immunization with a self-antigen in a Treg-, IL-10R-dependent manner [51, 52]. Maturation markers were restored however, in the presence of pro-inflammatory TLR3 signals [51], suggesting this type of DC tolerance could be overridden during an infection if necessary. Other TLR ligands such as CpG or co-administration of viruses and dendritic cells have helped override established T cell tolerance to tumors [53, 54].…”