期刊
IMMUNOLOGY AND CELL BIOLOGY
卷 93, 期 6, 页码 548-557出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/icb.2014.119
关键词
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资金
- National Health and Medical Research Council of Australia (NHMRC) [1037321, 1043414]
- Juvenile Diabetes Research Foundation (JDRF) [JDRF 112613, JDRF 447718]
- Melbourne International Research Scholarships (MIRS)
- Melbourne International Fee Remission Scholarship (MIFRS) from The University of Melbourne
- Walter and Eliza Hall Institute of Medical Research
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.
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