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J Leukoc Biol. 2014 Feb;95(2):325-36. doi: 10.1189/jlb.0113013. Epub 2013 Sep 30.

CD8+ dendritic cell-mediated tolerance of autoreactive CD4+ T cells is deficient in NOD mice and can be corrected by blocking CD40L.

Author information

1
1.Diabetes, Endocrinology, and Obesity Branch, NIDDK, NIH, Bldg. 10, CRC, West Labs, 5-5940, Bethesda, MD 20892, USA. tarbellk@niddk.nih.gov.

Abstract

DCs are important mediators of peripheral tolerance for the prevention of autoimmunity. Chimeric αDEC-205 antibodies with attached antigens allow in vivo antigen-specific stimulation of T cells by CD8(+) DCs, resulting in tolerance in nonautoimmune mice. However, it is not clear whether DC-mediated tolerance induction occurs in the context of ongoing autoimmunity. We assessed the role of CD8(+) DCs in stimulation of autoreactive CD4(+) T cells in the NOD mouse model of type 1 diabetes. Targeting of antigen to CD8(+) DCs via αDEC-205 led to proliferation and expansion of β-cell specific BDC2.5 T cells. These T cells also produced IL-2 and IFN-γ and did not up-regulate FoxP3, consistent with an activated rather than tolerant phenotype. Similarly, endogenous BDC peptide-reactive T cells, identified with I-A(g7) tetramers, did not become tolerant after antigen delivery via αDEC-205: no deletion or Treg induction was observed. We observed that CD8(+) DCs from NOD mice expressed higher surface levels of CD40 than CD8(+) DCs from C57BL/6 mice. Blockade of CD40-CD40L interactions reduced the number of BDC2.5 T cells remaining in mice, 10 days after antigen targeting to CD8 DCs, and blocked IFN-γ production by BDC2.5 T cells. These data indicate that the ability of autoreactive CD4(+) T cells to undergo tolerance mediated by CD8(+) DCs is defective in NOD mice and that blocking CD40-CD40L interactions can restore tolerance induction.

KEYWORDS:

CD40; DEC-205; peripheral tolerance; type 1 diabetes

PMID:
24082013
PMCID:
PMC3896656
DOI:
10.1189/jlb.0113013
[Indexed for MEDLINE]
Free PMC Article

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