title: Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes.
abstract: The adaptive immune repertoire plays a critical role in type 1 diabetes (T1D) pathogenesis. However, efforts to characterize B cell and T cell receptor (TCR) profiles in T1D subjects have been largely limited to peripheral blood sampling and restricted to known antigens. To address this, we collected pancreatic draining lymph nodes (pLN), "irrelevant" nonpancreatic draining lymph nodes, peripheral blood mononuclear cells (PBMC), and splenocytes from T1D subjects (n= 18) and control donors (n= 9) as well as pancreatic islets from 1 T1D patient; from these tissues, we collected purified CD4+conventional T cells (Tconv), CD4+Treg, CD8+T cells, and B cells. By conducting high-throughput immunosequencing of the TCR β chain (TRB) and B cell receptor (BCR) immunoglobulin heavy chain (IGH) on these samples, we sought to analyze the molecular signature of the lymphocyte populations within these tissues and of T1D. Ultimately, we observed a highly tissue-restricted CD4+repertoire, while up to 24% of CD8+clones were shared among tissues. We surveyed our data set for previously described proinsulin- and glutamic acid decarboxylase 65-reactive (GAD65-reactive) receptors, and interestingly, we observed a TRB with homology to a known GAD65-reactive TCR (clone GAD4.13) present in 7 T1D donors (38.9%), representing >25% of all productive TRB within Tconv isolated from the pLN of 1 T1D subject. These data demonstrate diverse receptor signatures at the nucleotide level and enriched autoreactive clones at the amino acid level, supporting the utility of coupling immunosequencing data with knowledge of characterized autoreactive receptors.
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA.
authors.forename: Howard R
authors.initials: HR
authors.lastname: Seay
authors.affiliation: Adaptive Biotechnologies Corporation, Seattle, Washington, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Yusko
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Rothweiler
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Posgai
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.affiliation: Adaptive Biotechnologies Corporation, Seattle, Washington, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Vignali
authors.affiliation: Adaptive Biotechnologies Corporation, Seattle, Washington, USA.
authors.forename: Ryan O
authors.initials: RO
authors.lastname: Emerson
authors.affiliation: Department of Information Sciences, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Kaddis
authors.affiliation: Department of Information Sciences, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Dave
authors.initials: D
authors.lastname: Ko
authors.affiliation: Barbara Davis Center for Childhood Diabetes and.
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Mia J
authors.initials: MJ
authors.lastname: Smith
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
authors.affiliation: Diabetes Research Institute and Departments of Medicine, Microbiology, and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pugliese
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.affiliation: Adaptive Biotechnologies Corporation, Seattle, Washington, USA.|Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Harlan S
authors.initials: HS
authors.lastname: Robins
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Brusko
mesh_terms: D001402:B-Lymphocytes / Q000145:classification*; D015496:CD4-Positive T-Lymphocytes / Q000145:classification*; D018414:CD8-Positive T-Lymphocytes / Q000145:classification*; D016022:Case-Control Studies; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains; D007963:Leukocytes, Mononuclear; D011947:Receptors, Antigen, B-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014018:Tissue Distribution
chemical_list: D007143:Immunoglobulin Heavy Chains; D011947:Receptors, Antigen, B-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta