title: Molecular anatomy and number of antigen specific CD8 T cells required to cause type 1 diabetes.
abstract: We quantified CD8 T cells needed to cause type 1 diabetes and studied the anatomy of the CD8 T cell/beta (β) cell interaction at the immunologic synapse. We used a transgenic model, in situ tetramer staining to distinguish antigen specific CD8 T cells from total T cells infiltrating islets and a variety of viral mutants selected for functional deletion(s) of various CD8 T cell epitopes. Twenty percent of CD8 T cells in the spleen were specific for all immunodominant and subdominant viral glycoprotein (GP) epitopes. CTLs to the immunodominant LCMV GP33-41 epitope accounted for 63% of the total (12.5% of tetramers). In situ hybridization analysis demonstrated only 1 to 2% of total infiltrating CD8 T cells were specific for GP33 CD8 T cell epitope, yet diabetes occurred in 94% of mice. The immunologic synapse between GP33 CD8 CTL and β cell contained LFA-1 and perforin. Silencing both immunodominant epitopes (GP33, GP276-286) in the infecting virus led to a four-fold reduction in viral specific CD8 CTL responses, negligible lymphocyte infiltration into islets and absence of diabetes.
authors.affiliation: Viral-Immunobiology Laboratory, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America. mbaobo@scripps.edu
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Edelmann
authors.forename: Dorian B
authors.initials: DB
authors.lastname: McGavern
authors.forename: Justin T
authors.initials: JT
authors.lastname: Cruite
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Welch
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D054992:Immunological Synapses / Q000235:genetics / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*
chemical_list: D016056:Immunodominant Epitopes; D016693:Receptors, Antigen, T-Cell, alpha-beta