Chapter III. Re-establishing Tolerance

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

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

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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