Dendritic cell-targeted pancreatic beta-cell antigen leads to conversion of self-reactive CD4(+) T cells into regulatory T cells and promotes immunotolerance in NOD mice.
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 beta-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.
Petzold
Cathleen
C
Immunotolerance in Regeneration, CRTD/DFG-Center for Regenerative Therapies Dresden, Institute of Physiological Chemistry, MTZ, Technical University Dresden, Fiedlerstr 42, 01307 Dresden, Germany.
Riewaldt
Julia
J
Koenig
Tina
T
Schallenberg
Sonja
S
Kretschmer
Karsten
K
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D007108:Immune Tolerance; D050417:Insulin-Secreting Cells / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D011994:Recombinant Proteins / Q000276:immunology
D000906:Antibodies; D001324:Autoantigens; D011994:Recombinant Proteins