title: CD4+ CD25+ regulatory T cells prevent type 1 diabetes preceded by dendritic cell-dominant invasive insulitis by affecting chemotaxis and local invasiveness of dendritic cells.
abstract: Development of type 1 diabetes (T1D) is preceded by invasive insulitis. Although CD4(+)CD25(+) regulatory T cells (nTregs) induce tolerance that inhibits insulitis and T1D, the in vivo cellular mechanisms underlying this process remain largely unclear. Using an adoptive transfer model and noninvasive imaging-guided longitudinal analyses, we found nTreg depletion did not affect systemic trafficking and tissue localization of diabetogenic CD4(+) BDC2.5 T (BDC) cells in recipient mice prior to development of T1D. In addition, neither the initial expansion/activation of BDC cells nor the number of CD11c(+) or NK cells in islets and pancreatic lymph nodes were altered. Unexpectedly, our results showed nTreg depletion led to accelerated invasive insulitis dominated by CD11c(+) dendritic cells (ISL-DCs), not BDC cells, which stayed in the islet periphery. Compared with control mice, the phenotype of ISL-DCs and their ability to stimulate BDC cells did not change during invasive insulitis development. However, ISL-DCs from nTreg-deficient recipient mice showed increased in vitro migration toward CCL19 and CCL21. These results demonstrated invasive insulitis dominated by DCs, not CD4(+) T cells, preceded T1D onset in the absence of nTregs, and suggested a novel in vivo function of nTregs in T1D prevention by regulating local invasiveness of DCs into islets, at least partly, through regulation of DC chemotaxis toward CCL19/CCL21 produced by the islets.
authors.affiliation: Department of Immunology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Mi-Heon
authors.initials: MH
authors.lastname: Lee
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Lee
authors.forename: Ivan
authors.initials: I
authors.lastname: Todorov
authors.forename: Chih-Pin
authors.initials: CP
authors.lastname: Liu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D054415:Chemokine CCL19 / Q000276:immunology / Q000378:metabolism; D054421:Chemokine CCL21 / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005434:Flow Cytometry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011236:Prediabetic State / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D039521:CD11c Antigen; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D053645:Interleukin-2 Receptor alpha Subunit