The role of dendritic cells in the mechanism of action of a peptide that ameliorates lupus in murine models
Open Access
- 4 August 2009
- journal article
- Published by Wiley in Immunology
- Vol. 128 (1pt2), e395-e405
- https://doi.org/10.1111/j.1365-2567.2008.02988.x
Abstract
Systemic lupus erythematosus (SLE) is characterized in its early stages by the expansion of autoreactive T cells that trigger B-cell activation with subsequent multi-organ injury. Dendritic cells (DCs) in lupus were found to display an aberrant phenotype with higher expression of the maturation markers major histocompatibility complex (MHC) class II, CD80 and CD86, as well as higher production of proinflammatory cytokines including interleukin-12 (IL-12), resulting in an increased ability to activate T cells. A peptide (hCDR1) based on the complementarity determining region-1 of an anti-DNA antibody ameliorated SLE in both induced and spontaneous lupus models by downregulating T-cell functions. Our objectives were to determine whether DCs play a role in promoting the beneficial effects of hCDR1. We showed here that treatment with hCDR1 lowered the expression levels of MHC class II, CD80 and CD86 on DCs. The latter effect was associated with downregulation of messenger RNA expression and secretion of IL-12, a cytokine that upregulated T-cell proliferation and interferon-γ (IFN-γ) secretion. Moreover, DCs derived from hCDR1-treated mice downregulated proliferation and IFN-γ secretion by T cells from untreated mice. Upregulation of transforming growth factor-β (TGF-β) secretion by T cells, following treatment with hCDR1, resulted in downregulation of IFN-γ production and contributed to the phenotypic changes and magnitude of IL-12 secretion by DCs. The ameliorating effects of hCDR1 are therefore mediated at least partially by the upregulated secretion of TGF-β by T cells that contribute to the induction of DCs with immature phenotype and suppressed functions. The resulting DCs further downregulate autoreactive T-cell functions.Keywords
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