title: IFN-α and CD46 stimulation are associated with active lupus and skew natural T regulatory cell differentiation to type 1 regulatory T (Tr1) cells.
abstract: Immune suppressive activities exerted by regulatory T-cell subsets have several specific functions, including self-tolerance and regulation of adaptive immune reactions, and their dysfunction can lead to autoimmune diseases and contribute to AIDS and cancer. Two functionally distinct regulatory T-cell subsets are currently identified in peripheral tissues: thymus-developed natural T regulatory cells (nTregs) controlling self-tolerance and antiinflammatory IL-10-secreting type 1 regulatory T cells (Tr1) derived from Ag-stimulated T cells, which regulate inflammation-dependent adaptive immunity and minimize immunopathology. We establish herein that cell contact-mediated nTreg regulatory function is inhibited by inflammation, especially in the presence of the complement C3b receptor (CD46). Instead, as with other T-cell subsets, the latter inflammatory conditions of stimulation skew nTreg differentiation to Tr1 cells secreting IL-10, an effect potentiated by IFN-α. The clinical relevance of these findings was verified in a study of 152 lupus patients, in which we showed that lupus nTreg dysfunction is not due to intrinsic defects but is rather induced by C3b stimulation of CD46 and IFN-α and that these immune components of inflammation are directly associated with active lupus. These results provide a rationale for using anti-IFN-α Ab immunotherapy in lupus patients.
authors: Institut National de la Santé et de la Recherche Médicale U976, Immunologie, Dermatologie, Oncologie, Hôpital Saint-Louis 75010 Paris, France.
authors: Hélène
authors: H
authors: Le Buanec
authors: Marie-Lise
authors: ML
authors: Gougeon
authors: Alexis
authors: A
authors: Mathian
authors: Pierre
authors: P
authors: Lebon
authors: Jean-Michel
authors: JM
authors: Dupont
authors: Gabriel
authors: G
authors: Peltre
authors: Patrice
authors: P
authors: Hemon
authors: Michel
authors: M
authors: Schmid
authors: Bernard
authors: B
authors: Bizzini
authors: Thomas
authors: T
authors: Künding
authors: Arsène
authors: A
authors: Burny
authors: Armand
authors: A
authors: Bensussan
authors: Zahir
authors: Z
authors: Amoura
authors: Robert C
authors: RC
authors: Gallo
authors: Daniel
authors: D
authors: Zagury
mesh_terms: D000911:Antibodies, Monoclonal; D002454:Cell Differentiation / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology*; D003179:Complement C3b / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism*; D016753:Interleukin-10 / Q000276:immunology; D007963:Leukocytes, Mononuclear; D016014:Linear Models; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051916:Membrane Cofactor Protein / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D017931:DNA Primers; D016898:Interferon-alpha; D051916:Membrane Cofactor Protein; D016753:Interleukin-10; D003179:Complement C3b