Cutting edge: merocytic dendritic cells break T cell tolerance to beta cell antigens in nonobese diabetic mouse diabetes.
In type 1 diabetes, the breach of central and peripheral tolerance results in autoreactive T cells that destroy insulin-producing, pancreatic beta cells. In this study, we identify a critical subpopulation of dendritic cells responsible for mediating both the cross-presentation of islet Ags to CD8(+) T cells and the direct presentation of beta cell Ags to CD4(+) T cells. These cells, termed merocytic dendritic cells (mcDCs), are more numerous in the NOD mouse and, when Ag-loaded, rescue CD8(+) T cells from peripheral anergy and deletion while stimulating islet-reactive CD4(+) T cells. When purified from the pancreatic lymph nodes of overtly diabetic NOD mice, mcDCs break peripheral T cell tolerance to beta cells in vivo and induce rapid onset type 1 diabetes in the young NOD mouse. Thus, the mcDC subset appears to represent the long-sought APC responsible for breaking peripheral tolerance to beta cell Ags in vivo.
Katz
Jonathan D
JD
Division of Endocrinology, Diabetes Research Center, Cincinnati Children's Research Foundation, Cincinnati, OH 45229, USA. jonathan.katz@cchmc.org
Ondr
Jennifer K
JK
Opoka
Robert J
RJ
Garcia
Zacharias
Z
Janssen
Edith M
EM
D000818:Animals; D000941:Antigens / Q000276:immunology*; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007370:Interferon Type I / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D000941:Antigens; D039481:CD11b Antigen; D016827:CD8 Antigens; D007370:Interferon Type I; D008565:Membrane Proteins; C084881:flt3 ligand protein