title: Pathogenic CD4⁺ T cells recognizing an unstable peptide of insulin are directly recruited into islets bypassing local lymph nodes.
abstract: In the nonobese diabetic mouse, a predominant component of the autoreactive CD4(+) T cell repertoire is directed against the B:9-23 segment of the insulin B chain. Previous studies established that the majority of insulin-reactive T cells specifically recognize a weak peptide-MHC binding register within the B:9-23 segment, that to the 12-20 register. These T cells are uniquely stimulated when the B:9-23 peptide, but not the insulin protein, is offered to antigen presenting cells (APCs). Here, we report on a T cell receptor (TCR) transgenic mouse (8F10) that offers important new insights into the biology of these unconventional T cells. Many of the 8F10 CD4(+) T cells escaped negative selection and were highly pathogenic. The T cells were directly recruited into islets of Langerhans, where they established contact with resident intra-islet APCs. Immunogenic insulin had to be presented in order for the T cells to localize and cause disease. These T cells bypassed an initial priming stage in the pancreatic lymph node thought to precede islet T cell entry. 8F10 T cells induced the production of antiinsulin antibodies and islets contained immunoglobulin (IgG) deposited on β cells and along the vessel walls.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: James F
authors.initials: JF
authors.lastname: Mohan
authors.forename: Boris
authors.initials: B
authors.lastname: Calderon
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
authors.forename: Emil R
authors.initials: ER
authors.lastname: Unanue
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology*; D005260:Female; D007328:Insulin / Q000737:chemistry / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D055550:Protein Stability; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
chemical_list: D007328:Insulin; D010455:Peptides; D011948:Receptors, Antigen, T-Cell