First Author | Price JD | Year | 2014 |
Journal | J Leukoc Biol | Volume | 95 |
Issue | 2 | Pages | 325-36 |
PubMed ID | 24082013 | Mgi Jnum | J:209536 |
Mgi Id | MGI:5568045 | Doi | 10.1189/jlb.0113013 |
Citation | Price JD, et al. (2014) CD8+ dendritic cell-mediated tolerance of autoreactive CD4+ T cells is deficient in NOD mice and can be corrected by blocking CD40L. J Leukoc Biol 95(2):325-36 |
abstractText | DCs are important mediators of peripheral tolerance for the prevention of autoimmunity. Chimeric alphaDEC-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 alphaDEC-205 led to proliferation and expansion of beta-cell specific BDC2.5 T cells. These T cells also produced IL-2 and IFN-gamma 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 alphaDEC-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-gamma 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. |