CD4+CD25+ regulatory T cells generated in response to insulin B:9-23 peptide prevent adoptive transfer of diabetes by diabetogenic T cells.
NOD mice have a relative deficiency of CD4+CD25+ regulatory T cells that could result in an inability to maintain peripheral tolerance. The aim of this study was to induce the generation of CD4+CD25+ regulatory T cells in response to autoantigens to prevent type 1 diabetes (T1D). We found that immunization of NOD mice with insulin B-chain peptide B:9-23 followed by 72 h in vitro culture with B:9-23 peptide induces generation of CD4+CD25+ regulatory T cells. Route of immunization has a critical role in the generation of these cells. Non-autoimmune mice BALB/c, C57BL/6 and NOR did not show up regulation of CD4+CD25+ regulatory T cells. These cells secreted large amounts of TGF-beta and TNF-alpha with little or no IFN-gamma and IL-10. Adoptive transfer of these CD4+CD25+ regulatory T cells into NOD-SCID mice completely prevented the adoptive transfer of disease by diabetogenic T cells. Although, non-self antigenic OVA (323-339) peptide immunization and in vitro culture with OVA (323-339) peptide does result in up regulation of CD4+CD25+ T cells, these cells did not prevent transfer of diabetes. Our study for the first time identified the generation of antigen-specific CD4+CD25+ regulatory T cells specifically in response to immunization with B:9-23 peptide in NOD mice that are capable of blocking adoptive transfer of diabetes. Our results suggest the possibility of using autoantigens to induce antigen-specific regulatory T cells to prevent and regulate autoimmune diabetes.
Mukherjee
Rinee
R
Department of Microbiology and Immunology, University of Western Ontario, and John P. Robarts Research Institute, University of Western Ontario, London, N6A 5C1, Ontario, Canada.
Chaturvedi
Pratibha
P
Qin
Hui-Yu
HY
Singh
Bhagirath
B
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004333:Drug Administration Routes; D005260:Female; D006029:Glycosuria / Q000209:etiology / Q000652:urine; D007108:Immune Tolerance / Q000276:immunology; D007328:Insulin / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000473:pathology; D019041:L-Selectin / Q000378:metabolism; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD / Q000276:immunology; D016513:Mice, SCID; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D015375:Receptors, Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014611:Vaccination; D000099192:CD69 Antigens
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015704:CD4 Antigens; D007328:Insulin; D007371:Interferon-gamma; D016753:Interleukin-10; D019041:L-Selectin; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D010047:Ovalbumin; D010446:Peptide Fragments; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens; C111390:OVA 323-339; C097877:insulin B (9-23)