DC specific Smad7 deficiency promotes differentiation of tolerogenic DCs able to attenuate EAE

Abstract

The immune network is a complex system for host defenses comprising various types of inflammatory and regulatory cells. Autoimmune diseases occur because of dysregulation in homeostasis caused by imbalance of these cells. The pattern of imbalance depends on the disease. Most autoimmune diseases are chronic, and the mechanism underlying this chronic nature is yet to be determined. Monoclonal antibody therapy is highly specific to the molecules targeted and is therefore highly effective. However, this therapy cannot be applied to all autoimmune diseases, and even the most effective therapy is incapable of completely inhibiting disease activity. Antigen-specific therapies have the ability to inhibit disease activity; however, their application is limited because of the presence of various disease-specific antigens. Regulatory cell therapies also have potential, but pose a plasticity problem. By focusing our research on experimental autoimmune encephalomyelitis (EAE), which is a multiple sclerosis (MS) model and normally initially has a relapse or remission course, followed by a progressive course, we can develop alternative therapies for the treatment of autoimmune diseases by exploring the mechanism of relapse and remission. From the phenomena that immunizing peptide itself determines the difference between monophasic-EAE and relapsingEAE, we found out that two-correlated non-genetic factors can shut down the reactivation in the EAE. One is kinetics and the component of CD4CD25 regulatory T cells (Treg), which are characterized by their later expansion after emerging of encephalitogenic T cells and by their subset expressing both CD69 and CD103 (=DP-Treg). DP-Treg is the most efficacious subset showing the highest Treg-compatible signatures with high antigen-specificity exerting stability due to downregulation of IL-6R expression, nevertheless with activated effector phenotype. The other is a hierarchy of encephalitogenic peptide itself to be immunized, which means that the more dominant peptide can develop acute EAE, the less relapse and re-induction of EAE occurs. This superiority of dominant peptide is characterized by specificity to itself, that is, it can suppress response to other peptides broadly and establish permanent remission. Peptide tolerance induced orally or intravenously could not get such wide suppression. Taken together, efficient induction of DP-Treg is correlated with superiority of self-peptide itself, suggesting ‘immunological homunculus’. This can be applied for treatment such as tissue-specific inverse vaccination for autoimmune diseases.