Original Data

Dendritic Cell-Targeted Pancreatic β-Cell Antigen Leads to Conversion of Self-Reactive CD4⁺ T Cells Into Regulatory T Cells and Promotes Immunotolerance in NOD Mice

Cathleen Petzold^1,2, Julia Riewaldt^1,2, Tina Koenig¹, Sonja Schallenberg¹, Karsten Kretschmer¹

Manuscript submitted February 22, 2010; resubmitted April 21, 2010; accepted May 3, 2010.

Keywords: type 1 diabetes, NOD mouse, autoimmunity, immune regulation, regulatory T cell, FoxP3, dendritic cell, DEC-205, BDC2.5 mimotope, proinsulin

Abstract

Studies employing T cell receptor transgenic T cells have convincingly shown that selective delivery of non-self model antigens to DEC-205⁺ dendritic cells (DCs) in the steady-state can induce Foxp3-expressing CD4⁺CD25⁺ regulatory T (Treg) cells from conventional CD4⁺CD25^-Foxp3^- T cells. Although of considerable clinical interest, the concept of DC-targeted de novo generation of antigen-specific Treg cells has not yet been evaluated for self-antigens and self-reactive CD4⁺ T cells in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Here, we show in proof-of-principle experiments that targeting a mimotope peptide to the endocytic receptor DEC-205 on DCs in NOD mice induces efficient conversion of pancreatic β-cell-reactive BDC2.5 CD4⁺ T cells into long-lived Foxp3⁺ Treg cells. Of note, conversion efficiency in normoglycemic and hyperglycemic mice with early diabetes onset was indistinguishable. While de novo generation of BDC2.5 Treg cells did not interfere with disease progression, anti-DEC-205-mediated targeting of whole proinsulin in prediabetic NOD mice substantially reduced the incidence of diabetes. These results suggest that promoting antigen-specific Treg cells in vivo might be a feasible approach towards cellular therapy in T1D.

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