Dendritic cells and the maintenance of self-tolerance
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UNIVERSITY OF PITTSBURGH IMMUNOLOGY 2011
Dendritic cells and the maintenance of self-tolerance Penelope A. Morel • Michael S. Turner
Penelope A. Morel
Published online: 30 June 2011 Ó Springer Science+Business Media, LLC 2011
Abstract Dendritic cells (DC) play important roles in the initiation of immune responses and in the maintenance of selftolerance. We have been studying the role of DC in the pathogenesis of type 1 diabetes and exploring the ability of specific DC subsets to prevent diabetes in non-obese diabetic (NOD) mice. DC presenting low doses of antigen are capable of inducing and expanding T-regulatory (Treg) cells that have potent suppressive function. We review here our recent findings in this area and highlight the ability of semi-mature therapeutic DC to induce Treg expansion in the absence of exogenous antigen. We discuss how the presentation of endogenous self-antigen by DC may represent a natural mechanism for peripheral self-tolerance that can be harnessed to prevent autoimmunity. Keywords
Dendritic cells Regulatory T cells Type 1 diabetes
Introduction The immune system exists in a precarious balance between preserving the ability to respond to pathogenic challenges while maintaining tolerance to self-tissues. T cells that express receptors with strong affinity for peptides derived from self-proteins are deleted in the thymus through the process of negative selection, a process mediated by dendritic cells (DC), and medullary epithelial cells in the thymus. Some self-reactive CD4? T cells differentiate into immunosuppressive regulatory T (Treg) cells, and it is thought that thymic DC, presenting self-antigens, are responsible for providing the necessary signals [1]. Treg arising in thymus are known as natural Treg (nTreg), and
P. A. Morel (&) M. S. Turner Departments of Immunology and Medicine, University of Pittsburgh, 200 Lothrop Street, BST E1048, Pittsburgh, PA 15261, USA e-mail: [email protected] Present Address: M. S. Turner Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
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they express the transcription factors Helios [2] and Foxp3, necessary for the maintenance of their suppressive function [3]. Although the process of negative selection is effective in preventing autoreactivity, some self-reactive T cells escape to the periphery where they are kept in check through various mechanisms of peripheral tolerance. These include deletion, induction of anergy, and suppression via the action of Treg cells. DC, in peripheral tissues and lymph nodes, present antigen to naı¨ve T cells and, depending on the context, induce T-cell activation and differentiation into specific T-helper (Th) subsets. The factors influencing the differentiation of Th cells include the antigen dose, costimulatory molecule expression, and the secretion of cytokines. Thus, Th1 cell differentiation requires a high dose of antigen and the secretion of IL-12p70 and IFN-c [4], whereas Th17 cells are induced by the presence of IL-6, TGF-b, IL-21, and IL-23 [5]. In addition, T cells can be induced to dif
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