Chapter III. Re-establishing Tolerance

Rev Diabet Stud, 2012, 9(4):305-318 DOI 10.1900/RDS.2012.9.305

Targeted Antigen Delivery to DEC-205+ Dendritic Cells for Tolerogenic Vaccination

Cathleen Petzold1, Sonja Schallenberg2, Joel N.H. Stern3, Karsten Kretschmer2

1Immunotolerance in Regeneration, Center for Regenerative Therapies Dresden, Dresden, Germany
2Immunotolerance in Regeneration, Center for Regenerative Therapies, Dresden, Germany
3Department of Cancer Immunology and AIDS, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
Address correspondence to: Karsten Kretschmer, e-mail: karsten.kretschmer@crt-dresden.de

Manuscript submitted December 22, 2012; resubmitted February 1, 2013; accepted February 7, 2013.

Keywords: type 1 diabetes, immune tolerance, dendritic cell, regulatory T cell, DEC-205, Foxp3

Abstract

Dendritic cells (DCs) and Foxp3-expressing CD4+ regulatory T (Treg) cells play non-redundant roles in the maintenance of peripheral tolerance to self-antigens, thereby preventing fatal autoimmunity. A common hallmark of intra- and extra-thymic Treg cell lineage commitment is the induction of Foxp3 expression as a consequence of appropriate T cell receptor engagement with MHC class II:agonist ligand. It has now become increasingly clear that agonist ligand presentation by immature DCs in the steady state induces T cell tolerance by both recessive and dominant mechanisms, rather than promoting productive T helper cell responses. In this context, the ability of steady-state DCs to promote the extrathymic conversion of initially naïve CD4+Foxp3- T cells into Foxp3+ Treg cells is of particular interest as it provides novel perspectives to enhance antigen-specific Treg cell function in clinical settings of unwanted immunity, such as β-cell autoimmunity.

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