title: DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype.
abstract: Recently, we have identified proinsulin (P-Ins)(73-90) as an immunodominant T cell epitope of HLA-DRB1*0401 (DR4) subjects with beta-islet cell autoimmunity and of HLA-DR4/CD4 double-transgenic mice immunized with human P-Ins. We have compared the fine specificities of one human CD4 T cell clone and two mouse T cell hybridoma clones recognizing this epitope, and, although these three clones all recognized the same core region (LALEGSLQK), there were major differences in how they interacted with the peptide (p)/HLA complex, reflecting the fact that human P-Ins is a foreign antigen in the mouse and an autoantigen in the type 1 diabetes patient. The human T cell clone was forkhead transcription factor 3 (Foxp3)-positive, a marker for regulatory T cell lineages, and secreted predominantly IL-5, IL-10, and low levels of IFNgamma in response to P-Ins(73-90). This finding is compatible with the previously detected regulatory cytokine pattern in subjects with beta-cell autoimmunity. However, added N- or C-terminal amino acids drastically changed HLA and tetramer binding capacity as well as T cell reactivity and the cytokine phenotype of the P-Ins(73-90)-specific human CD4 T cell clone, suggesting a potential for this P-Ins epitope as a target for therapeutic intervention in HLA-DR4-positive humans with beta-islet cell autoimmunity or recent-onset type 1 diabetes.
authors.affiliation: Department of Internal Medicine I, Division of Endocrinology, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Ivana
authors.initials: I
authors.lastname: Durinovic-Belló
authors.forename: Silke
authors.initials: S
authors.lastname: Rosinger
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Olson
authors.forename: Mauro
authors.initials: M
authors.lastname: Congia
authors.forename: Regina C
authors.initials: RC
authors.lastname: Ahmad
authors.forename: Mathias
authors.initials: M
authors.lastname: Rickert
authors.forename: Johannes
authors.initials: J
authors.lastname: Hampl
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
authors.forename: Sascha
authors.initials: S
authors.lastname: Al Dahouk
authors.forename: Thomas
authors.initials: T
authors.lastname: Kamradt
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Maeurer
authors.forename: Carol
authors.initials: C
authors.lastname: Nhan
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Constantin
authors.initials: C
authors.lastname: Polychronakos
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.forename: Wolfram
authors.initials: W
authors.lastname: Karges
authors.forename: Hugh O
authors.initials: HO
authors.lastname: McDevitt
authors.forename: Grete
authors.initials: G
authors.lastname: Sønderstrup
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000939:Epitopes; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D010641:Phenotype; D011384:Proinsulin / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000596:Amino Acids; D000939:Epitopes; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D010446:Peptide Fragments; D011384:Proinsulin