title: Extreme Th1 bias of invariant Valpha24JalphaQ T cells in type 1 diabetes.
abstract: Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) is a disease controlled by the major histocompatibility complex (MHC) which results from T-cell-mediated destruction of pancreatic beta-cells. The incomplete concordance in identical twins and the presence of autoreactive T cells and autoantibodies in individuals who do not develop diabetes suggest that other abnormalities must occur in the immune system for disease to result. We therefore investigated a series of at-risk non-progressors and type 1 diabetic patients (including five identical twin/triplet sets discordant for disease). The diabetic siblings had lower frequencies of CD4-CD8- Valpha24JalphaQ+ T cells compared with their non-diabetic sibling. All 56 Valpha24JalphaQ+ clones isolated from the diabetic twins/triplets secreted only interferon (IFN)-gamma upon stimulation; in contrast, 76 of 79 clones from the at-risk non-progressors and normals secreted both interleukin (IL)-4 and IFN-gamma. Half of the at-risk non-progressors had high serum levels of IL-4 and IFN-gamma. These results support a model for IDDM in which Thl-cell-mediated tissue damage is initially regulated by Valpha24JalphaQ+ T cells producing both cytokines; the loss of their capacity to secrete IL-4 is correlated with IDDM.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Wilson
authors.forename: S C
authors.initials: SC
authors.lastname: Kent
authors.forename: K T
authors.initials: KT
authors.lastname: Patton
authors.forename: T
authors.initials: T
authors.lastname: Orban
authors.forename: R A
authors.initials: RA
authors.lastname: Jackson
authors.forename: M
authors.initials: M
authors.lastname: Exley
authors.forename: S
authors.initials: S
authors.lastname: Porcelli
authors.forename: D A
authors.initials: DA
authors.lastname: Schatz
authors.forename: M A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: S P
authors.initials: SP
authors.lastname: Balk
authors.forename: J L
authors.initials: JL
authors.lastname: Strominger
authors.forename: D A
authors.initials: DA
authors.lastname: Hafler
mesh_terms: D018949:Antigens, CD1 / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018450:Disease Progression; D004200:Diseases in Twins; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D018655:Lymphocyte Count; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014310:Triplets; D014430:Twins, Monozygotic
chemical_list: D018949:Antigens, CD1; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D007371:Interferon-gamma