title: Intranasal peptide-induced tolerance and linked suppression: consequences of complement deficiency.
abstract: A role for complement, particularly the classical pathway, in the regulation of immune responses is well documented. Deficiencies in C1q or C4 predispose to autoimmunity, while deficiency in C3 affects the suppression of contact sensitization and generation of oral tolerance. Complement components including C3 have been shown to be required for both B-cell and T-cell priming. The mechanisms whereby complement can mediate these diverse regulatory effects are poorly understood. Our previous work, using the mouse minor histocompatibility (HY) model of skin graft rejection, showed that both C1q and C3 were required for the induction of tolerance following intranasal peptide administration. By comparing tolerance induction in wild-type C57BL/6 and C1q-, C3-, C4- and C5-deficient C57BL/6 female mice, we show here that the classical pathway components including C3 are required for tolerance induction, whereas C5 plays no role. 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.
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College London, London, UK.
authors.forename: Liliane
authors.initials: L
authors.lastname: Fossati-Jimack
authors.forename: Guang Sheng
authors.initials: GS
authors.lastname: Ling
authors.forename: Lucie
authors.initials: L
authors.lastname: Baudino
authors.forename: Marta
authors.initials: M
authors.lastname: Szajna
authors.forename: Kiruthika
authors.initials: K
authors.lastname: Manivannan
authors.forename: Jade Chen
authors.initials: JC
authors.lastname: Zhao
authors.forename: Robert
authors.initials: R
authors.lastname: Midgley
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chai
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Simpson
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.forename: Diane
authors.initials: D
authors.lastname: Scott
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D003165:Complement System Proteins / Q000235:genetics* / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D006182:H-Y Antigen / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D006182:H-Y Antigen; D010455:Peptides; D003165:Complement System Proteins; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: complement; dendritic cells; regulatory T cells; rodent; tolerance