Immunization with “self” peptide induces a novel phenotype of splenic dendritic cells contributing to peripheral tolerance (48.10)

Abstract

Abstract A 100mer peptide (MUC1p) derived from the tumor associated antigen MUC1 is seen as “self” by the immune system of MUC1 Tg mice. TCR.Tg CD4+ T cells specific for MUC1 proliferate less in MUC1 Tg mice after vaccination with DC loaded with MUC1p (DC/MUC1p) relative to WT. We performed gene array on splenic RNA from WT and Tg mice vaccinated with DC/MUC1p to globally query mechanisms of peripheral tolerance to MUC1p. Expression of well-characterized pancreatic proteases (Trypsin, Elastase, CPB1) was dramatically down regulated in DC from immunized MUC1 Tg mice relative to WT, providing a signature of ensuing tolerance to self-peptide. Additionally, there was a decrease in the number of splenic DC in MUC1 Tg mice concurrent with an increase in the number of NK cells, in an IL-10 dependent fashion. IL-10 is also required to mediate down-regulation of proteases in DC linking enzyme expression with immunogenicity. Preliminary data suggest that this IL-10 is derived from increased numbers of MDSC in the spleens of immunized MUC1 Tg mice. Splenic DC from DC/MUC1p immunized MUC1 Tg mice migrate shorter distances ex vivo compared to DC recovered from WT, suggesting impaired ability to home in vivo. These DC produce less IL-12p40 and more Aldh1 compared to WT DC and express less CD40, CD86 and MHCII. Finally, DC from DC/MUC1p vaccinated MUC1 Tg mice differentiate naïve CD4+ T cells into Foxp3+ Treg in an antigen-specific manner ex vivo more effectively than DC recovered from WT mice.