Intranasal peptide-induced tolerance and linked suppression: consequences of complement deficiency.
Bottom Line: C3-deficient mice failed to generate a functional regulatory T (Treg) -dendritic cell (DC) tolerogenic loop required for tolerance induction.This was related to the inability of C3-deficient DC to up-regulate the arginine-consuming enzyme, inducible nitric oxide synthase (Nos-2), in the presence of antigen-specific Treg cells and peptide, leading to reduced Treg cell generation.Our findings demonstrate that the classical pathway and C3 play a critical role in the peptide-mediated induction of tolerance to HY by modulating DC function.
Affiliation: Centre for Complement and Inflammation Research, Imperial College London, London, UK.Show MeSH
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Mentions: The initial phase in this model of tolerance induction is the presentation of the peptide by antigen-presenting cells, most likely DC. Twenty-four hours after the i.n. administration the peptide is found in CD11c-positive DC in spleen, and in peripheral and cervical draining lymph nodes.24 To determine whether complement affected the peptide dissemination and/or presentation, B6 WT and B6.C3–/– female mice were given i.n. HY-AbDby peptide. Twenty-four hours later splenic DC were isolated and used to stimulate HY-AbDby-specific CD4+ T cells from TCR transgenic Marilyn mice (Marilyn T cells). The purity, percentage of CD8+/CD8− DC and expression levels of CD40, CD86 and H2-Ab were similar (data not shown). Regardless of their complement status splenic, DC from the peptide-treated mice were equally able to stimulate the proliferation of the Marilyn T cells (Fig.2); hence complement does not influence the distribution or initial presentation of the peptide.
Affiliation: Centre for Complement and Inflammation Research, Imperial College London, London, UK.