title: Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health.
abstract: According to the quality of response they mediate, autoreactive T cells recognizing islet beta cell peptides could represent both disease effectors in the development of type 1 diabetes (T1DM) and directors of tolerance in nondiabetic individuals or those undergoing preventative immunotherapy. A combination of the rarity of these cells, inadequate technology, and poorly defined epitopes, however, has hampered examination of this paradigm. We have identified a panel of naturally processed islet epitopes by direct elution from APCs bearing HLA-DR4. Employing these epitopes in a sensitive, novel cytokine enzyme-linked immunosorbent spot assay, we show that the quality of autoreactive T cells in patients with T1DM exhibits extreme polarization toward a proinflammatory Th1 phenotype. Furthermore, we demonstrate that rather than being unresponsive, the majority of nondiabetic, HLA-matched control subjects also manifest a response against islet peptides, but one that shows extreme T regulatory cell (Treg, IL-10-secreting) bias. We conclude that development of T1DM depends on the balance of autoreactive Th1 and Treg cells, which may be open to favorable manipulation by immune intervention.
authors.affiliation: Department of Immunobiology, Guy's, King's and St. Thomas' School of Medicine, King's College London, Guy's Campus, London, United Kingdom.
authors.forename: Sefina
authors.initials: S
authors.lastname: Arif
authors.forename: Timothy I
authors.initials: TI
authors.lastname: Tree
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Astill
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Tremble
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bishop
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dayan
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
mesh_terms: D017668:Age of Onset; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011384:Proinsulin / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D015804:HLA-DR4 Antigen; C096322:ICA512 autoantibody; D010455:Peptides; D015847:Interleukin-4; D007371:Interferon-gamma; D011384:Proinsulin