title: Population dynamics of islet-infiltrating cells in autoimmune diabetes.
abstract: Type-1 diabetes in the nonobese diabetic (NOD) mouse starts with an insulitis stage, wherein a mixed population of leukocytes invades the pancreas, followed by overt diabetes once enough insulin-producing β-cells are destroyed by invading immunocytes. Little is known of the dynamics of lymphocyte movement into the pancreas during disease progression. We used the Kaede transgenic mouse, whose photoconvertible fluorescent reporter permits noninvasive labeling and subsequent tracking of immunocytes, to investigate pancreatic infiltrate dynamics and the requirement for antigen specificity during progression of autoimmune diabetes in the unmanipulated NOD mouse. Our results indicate that the insulitic lesion is very open with constant cell influx and active turnover, predominantly of B and T lymphocytes, but also CD11b(+)c(+) myeloid cells. Both naïve- and memory-phenotype lymphocytes trafficked to the insulitis, but Foxp3(+) regulatory T cells circulated less than their conventional CD4(+) counterparts. Receptor specificity for pancreatic antigens seemed irrelevant for this homing, because similar kinetics were observed in polyclonal and antigen-specific transgenic contexts. This "open" configuration was also observed after reversal of overt diabetes by anti-CD3 treatment. These results portray insulitis as a dynamic lesion at all stages of disease, continuously fed by a mixed influx of immunocytes, and thus susceptible to evolve over time in response to immunologic or environmental influences.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Angela M
authors.initials: AM
authors.lastname: Magnuson
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114; and.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Thurber
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114; and.
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Kohler
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114; and.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115 cbdm@hms.harvard.edu.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology*; D018450:Disease Progression; D007156:Immunologic Memory; D007515:Islets of Langerhans / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
keywords: Treg; cell tracer; reporter