Expression of CD40 identifies a unique pathogenic T cell population in type 1 diabetes.
Juvenile diabetes (type 1) is an autoimmune disease in which CD4(+) T cells play a major role in pathogenesis characterized by insulitis and beta cell destruction leading to clinical hyperglycemia. To date, no marker for autoimmune T cells has been described, although it was previously demonstrated that autoimmune mice have a large population of CD4(+) cells that express CD40. We show here that established, diabetogenic T cell clones of either the Th1 or Th2 phenotype are CD40-positive, whereas nondiabetogenic clones are CD40-negative. CD40 functionally signals T cell clones, inducing rapid activation of the transcription factor NFkappaB. We show that autoimmune diabetes-prone nonobese diabetic mice have high levels of CD40(+)CD4(+) T cells in the thymus, spleen, and importantly, in the pancreas. Finally, as demonstrated by adoptive transfers, CD4(+)CD40(+) cells infiltrate the pancreatic islets causing beta-cell degranulation and ultimately diabetes.
Wagner
David H
DH
Webb-Waring Institute for Cancer, Aging, and Antioxidant Research, Division of Pulmonary Medicine, Department of Medicine, Barbara Davis Childhood Diabetes Center, University of Colorado Health Science Center, Denver, CO 80262, USA. david.wagner@uchsc.edu
Vaitaitis
Gisela
G
Sanderson
Richard
R
Poulin
Michelle
M
Dobbs
Cathleen
C
Haskins
Kathryn
K
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D015704:CD4 Antigens / Q000032:analysis / Q000378:metabolism; D019013:CD40 Antigens / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D015704:CD4 Antigens; D019013:CD40 Antigens; D016328:NF-kappa B