Published online before print April 6, 2009

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(American Journal of Pathology. 2009;174:1575-1587.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080987

Review

Surveillance of Antigen-Presenting Cells by CD4+CD25+ Regulatory T Cells in Autoimmunity

Immunopathogenesis and Therapeutic Implications

Sébastien André^*, David F. Tough, Sébastien Lacroix-Desmazes^*, Srini V. Kaveri^* and Jagadeesh Bayry^*

From the Institut National de la Santé et de la Recherche Médicale,^* Paris, France; the Centre de Recherche des Cordeliers, Equipe 16- Immunopathology and Therapeutic Immunointervention, Université Pierre et Marie Curie, Paris, France; the Université Paris Descartes, Paris, France; and Immuno-Inflammation, Centre of Excellence in Drug Discovery, GlaxoSmithKline, Stevenage, United Kingdom

Abstract

CD4+CD25+ regulatory T cells (Tregs) play a critical role in preventing immune aggression. One way in which Tregs exert immune surveillance activities is by modifying the function of antigen presenting cells (APCs) such as dendritic cells, macrophages, and B cells. Tregs can induce apoptosis of APCs or inhibit their activation and function, thereby regulating subsequent innate and adaptive immune responses. These actions of Tregs are mediated by both soluble factors (interleukin [IL]-10, transforming growth factor-β, perforins, granzymes) and cell-associated molecules (cytotoxic T lymphocyte antigen 4, lymphocyte activation gene-3, CD18, neuropilin-1, LFA-1/CD11a, CD39), of which cytotoxic T lymphocyte antigen 4 has a key role. However, in autoimmunity, chronically activated APCs under the influence of intracellular signaling pathways, such as phosphatidyl inositol 3 kinase, JAK-STAT, MAPK, and nuclear factor-B pathways, can escape surveillance by Tregs, leading to the activation of T cells that are refractory to suppression by Tregs. Moreover, APCs and APC-derived inflammatory cytokines such as tumor necrosis factor, IL-6, IL-1β, and IL-23 can render Tregs defective and can also reciprocally enhance the activity of the IL-17-producing pathogenic Th17 T cell subset. Emerging knowledge of the importance of APC-Treg interactions in maintaining immune tolerance and aberrations in this cross talk in autoimmune diseases provides a rationale for therapeutic approaches specifically targeting this axis of the immune system.