The Role of Dendritic Cell Subsets and Innate Immunity in the Pathogenesis of Type 1 Diabetes and Other Autoimmune Diseases.

Jeffrey D Price,Kristin V Tarbell

doi:10.3389/fimmu.2015.00288

Abstract

Dendritic cells (DCs) are key antigen-presenting cells that have an important role in autoimmune pathogenesis. DCs control both steady-state T cell tolerance and activation of pathogenic responses. The balance between these two outcomes depends on several factors, including genetic susceptibility, environmental signals that stimulate varied innate responses, and which DC subset is presenting antigen. Although the specific DC phenotype can diverge depending on the tissue location and context, there are four main subsets identified in both mouse and human: conventional cDC1 and cDC2, plasmacytoid DCs, and monocyte-derived DCs. In this review, we will discuss the role of these subsets in autoimmune pathogenesis and regulation, as well as the genetic and environmental signals that influence their function. Specific topics to be addressed include impact of susceptibility loci on DC subsets, alterations in DC subset development, the role of infection- and host-derived innate inflammatory signals, and the role of the intestinal microbiota on DC phenotype. The effects of these various signals on disease progression and the relative effects of DC subset composition and maturation level of DCs will be examined. These areas will be explored using examples from several autoimmune diseases but will focus mainly on type 1 diabetes.

Highlights

Dendritic cells (DCs) play a vital role in host immunity by inducing innate inflammatory responses to pathogens, efficiently priming naïve T cells, activating memory T cells, and promoting B cell activation
This review describes recent advances in our knowledge of the differential roles of particular DC subsets and activated monocytes for tolerance induction
Conventional DCs: CD8+ cDC1 and CD11b+ DCIR2+ cDC2 The different roles of specific DC subsets in eliciting autoimmune pathogenic responses versus tolerance induction are likely to be important for successful immunotherapy. cDC1s and cDC2s are primarily located in distinct anatomical locations in lymphoid tissues and process and present antigen on MHCI and MHCII differently, and cause different stimulation of CD8+ and CD4+ T cells [29]

Summary

Introduction

Dendritic cells (DCs) play a vital role in host immunity by inducing innate inflammatory responses to pathogens, efficiently priming naïve T cells, activating memory T cells, and promoting B cell activation. Initial studies of DC ablation showed that decreased DCs-induced autoimmunity because of an inability to maintain Tregs [5], yet other studies have demonstrated that a loss of DCs decreased disease severity by blocking activation of pathogenic cells [6, 7] In both autoimmune patients and murine models of autoimmunity, DCs exhibit alterations in phenotype or function that could be due to underlying genetic defects or the chronic inflammatory environment, and can affect both the initiation of disease and later failure of tolerance mechanisms that lead to tissue destruction such as loss of insulin-producing beta cells in T1D (Figure 1). This review describes recent advances in our knowledge of the differential roles of particular DC subsets and activated monocytes for tolerance induction

The Role of Specific DC Subsets in Autoimmunity

May expand effector T cells

The Role of DC Development in Autoimmunity

Effects of DC Maturation Thresholds on Development of Autoimmunity

Blocking DC Alterations to Maintain T Cell Tolerance

Implications for Designing New Therapies to Treat Autoimmunity