title: Neonatal activation of CD28 signaling overcomes T cell anergy and prevents autoimmune diabetes by an IL-4-dependent mechanism.
abstract: Optimal T cell responsiveness requires signaling through the T cell receptor (TCR) and CD28 costimulatory receptors. Previously, we showed that T cells from autoimmune nonobese diabetic (NOD) mice display proliferative hyporesponsiveness to TCR stimulation, which may be causal to the development of insulin-dependent diabetes mellitus (IDDM). Here, we demonstrate that anti-CD28 mAb stimulation restores complete NOD T cell proliferative responsiveness by augmentation of IL-4 production. Whereas neonatal treatment of NOD mice with anti-CD28 beginning at 2 wk of age inhibits destructive insulitis and protects against IDDM by enhancement of IL-4 production by islet-infiltrating T cells, administration of anti-CD28 beginning at 5-6 wk of age does not prevent IDDM. Simultaneous anti-IL-4 treatment abrogates the preventative effect of anti-CD28 treatment. Thus, neonatal CD28 costimulation during 2-4 wk of age is required to prevent IDDM, and is mediated by the generation of a Th2 cell-enriched nondestructive environment in the pancreatic islets of treated NOD mice. Our data support the hypothesis that a CD28 signal is requisite for activation of IL-4-producing cells and protection from IDDM.
authors.affiliation: Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.
authors.forename: G A
authors.initials: GA
authors.lastname: Arreaza
authors.forename: M J
authors.initials: MJ
authors.lastname: Cameron
authors.forename: A
authors.initials: A
authors.lastname: Jaramillo
authors.forename: B M
authors.initials: BM
authors.lastname: Gill
authors.forename: D
authors.initials: D
authors.lastname: Hardy
authors.forename: K B
authors.initials: KB
authors.lastname: Laupland
authors.forename: M J
authors.initials: MJ
authors.lastname: Rapoport
authors.forename: P
authors.initials: P
authors.lastname: Zucker
authors.forename: S
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: S W
authors.initials: SW
authors.lastname: Chensue
authors.forename: H Y
authors.initials: HY
authors.lastname: Qin
authors.forename: B
authors.initials: B
authors.lastname: Singh
authors.forename: T L
authors.initials: TL
authors.lastname: Delovitch
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018106:CD28 Antigens / Q000378:metabolism*; D002470:Cell Survival; D017635:Clonal Anergy; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D007116:Immunization, Passive; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D007376:Interleukin-2; D015847:Interleukin-4; D005968:Glutamate Decarboxylase