title: Peak inflammation in atherosclerosis, primary biliary cirrhosis and autoimmune arthritis is counter-intuitively associated with regulatory T cell enrichment.
abstract: Regulatory T cells (Treg) influence the development of autoimmunity and their use is increasingly proposed for clinical applications. The well-characterized suppressive potential of Treg frequently leads to the assumption that Treg presence in prevailing numbers is indicative of immunosuppression. We hypothesized that this assumption may be false. We examined models of three different diseases caused by organ-specific autoimmune responses: primary biliary cirrhosis, atherosclerosis and rheumatoid arthritis (RA). We examined indicators of relative abundance of Treg compared to pro-inflammatory T cells, during peak inflammation. In all cases, the results were compatible with a relative enrichment of Treg at the site of inflammation or its most proximal draining lymph node. Conversely, in healthy mice or mice successfully protected from disease via a Treg-mediated mechanism, the data did not suggest that any Treg accumulation was occurring. This counter-intuitive finding may appear to be at odds with the immunosuppressive nature of Treg. Yet extensive previous studies in RA show that an accumulation of Treg occurs at peak inflammation, albeit without resulting in suppression, as the Treg suppressive function is overcome by the cytokine-rich environment. We suggest that this is a ubiquitous feature of autoimmune inflammation. Treg abundance in patient samples is increasingly used as an indicator of a state of immunosuppression. We conclude that this strategy should be revisited as it may potentially be a source of misinterpretation.
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (Milano), Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Garetto
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (Milano), Italy.
authors.forename: Anna Elisa
authors.initials: AE
authors.lastname: Trovato
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (Milano), Italy; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Manzoni 56, Rozzano (Milan), Italy.
authors.forename: Ana
authors.initials: A
authors.lastname: Lleo
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Sala
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (Milano), Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Martini
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Betz
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy; Center for the Study of Atherosclerosis, Società Italiana Studio Aterosclerosi, Ospedale Bassini, Cinisello Balsamo, Italy; The Blizard Institute, Centre for Diabetes, Barts and The London School of Medicine & Dentistry, Queen Mary University, London, UK.
authors.forename: Giuseppe D
authors.initials: GD
authors.lastname: Norata
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (Milano), Italy; Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (Milano), Italy; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Manzoni 56, Rozzano (Milan), Italy. Electronic address: marinos.kallikourdis@humanitasresearch.it.
authors.forename: Marinos
authors.initials: M
authors.lastname: Kallikourdis
mesh_terms: D000818:Animals; D001168:Arthritis / Q000276:immunology*; D050197:Atherosclerosis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D049109:Cell Proliferation; D004036:Diet, Atherogenic / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D011973:Receptors, LDL
keywords: Atherosclerosis; Autoimmunity; Inflammation; Primary biliary cirrhosis; Regulatory T cells; Rheumatoid arthritis