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: Hélène Le Buanec, Marie-Lise Gougeon, Alexis Mathian, Pierre Lebon, Jean-Michel Dupont, Gabriel Peltre, Patrice Hemon, Michel Schmid, Bernard Bizzini, Thomas Künding, Arsène Burny, Armand Bensussan, Zahir Amoura, Robert C Gallo, Daniel Zagury
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 47 Pg. 18995-9000 (Nov 22 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 22065791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• DNA Primers
• Interferon-alpha
• Membrane Cofactor Protein
• Interleukin-10
• Complement C3b

Topics

• Antibodies, Monoclonal
• Cell Differentiation (immunology)
• Complement Activation (immunology)
• Complement C3b (immunology)
• DNA Primers (genetics)
• Flow Cytometry
• Humans
• Immunotherapy (methods)
• Interferon-alpha (immunology, metabolism)
• Interleukin-10 (immunology)
• Leukocytes, Mononuclear
• Linear Models
• Lupus Erythematosus, Systemic (immunology)
• Membrane Cofactor Protein (immunology, metabolism)
• Real-Time Polymerase Chain Reaction
• T-Lymphocytes, Regulatory (immunology)