title: NOD mice are functionally deficient in the capacity of cross-presentation.
abstract: Cross-presentation by CD8(+) conventional dendritic cells (cDCs) is involved in the maintenance of peripheral tolerance and this process is termed cross-tolerance. Previous reports showed that non-obese diabetic (NOD) mice have reduced number of splenic CD8(+) cDCs compared with non-diabetic strains, and that the administration of Flt3L to enhance DC development resulted in reduced diabetes incidence. As CD8(+) cDCs are the most efficient antigen cross-presenting cells, it was assumed that reduced cross-presentation by non-activated, tolerogenic CD8(+) cDC predisposes to autoimmune diabetogenesis. Here we show for the first time that indeed NOD mice have a defect in autoantigen cross-presentation capacity. First, we showed that NOD CD8(+) cDCs were less sensitive to iatrogenic cytochrome c, which had previously been shown to selectively deplete CD8(+) cDCs that functionally cross-present. Second, we found that proliferation of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific CD8(+) T cells was impaired in NOD compared with non-obese diabetes resistant mice after immunization with cell associated recombinant fusion protein containing the cognate IGRP peptide. This study, therefore, suggests that the reduced number of CD8(+) cDCs in NOD mice, coupled with the reduced capacity to cross-present self-antigens, reduces the overall capacity to maintain peripheral tolerance in the spontaneous autoimmune type 1 diabetes mice.
authors.affiliation: Molecular Immunology Division of The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
authors.forename: Chin-Nien
authors.initials: CN
authors.lastname: Lee
authors.affiliation: Immunology Division of The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
authors.affiliation: Immunology Division of The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Shortman
authors.affiliation: 1] Molecular Immunology Division of The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University School of Medicine, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D016827:CD8 Antigens / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005952:Glucose-6-Phosphatase / Q000737:chemistry / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D016130:Immunophenotyping; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D001324:Autoantigens; D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse