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. 2015 Aug;220(8):1025-9.
doi: 10.1016/j.imbio.2015.02.006. Epub 2015 Feb 26.

Peak inflammation in atherosclerosis, primary biliary cirrhosis and autoimmune arthritis is counter-intuitively associated with regulatory T cell enrichment

Stefano Garetto  1 , Anna Elisa Trovato  1 , Ana Lleo  2 , Federica Sala  3 , Elisa Martini  1 , Alexander G Betz  4 , Giuseppe D Norata  5 , Pietro Invernizzi  6 , Marinos Kallikourdis  7
Affiliations

Peak inflammation in atherosclerosis, primary biliary cirrhosis and autoimmune arthritis is counter-intuitively associated with regulatory T cell enrichment

Stefano Garetto et al. Immunobiology. 2015 Aug.

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.

Keywords: Atherosclerosis; Autoimmunity; Inflammation; Primary biliary cirrhosis; Regulatory T cells; Rheumatoid arthritis.

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Figures

Fig. 1
Fig. 1
Regulatory T cell enrichment during peak inflammation in mouse models of organ-specific autoimmunity. (A) Atherosclerosis: The ratio of Treg to Teff, as indicated by the relative levels of FoxP3 to CD4 mRNA measured by real-time qPCR analysis, in aortic samples from C57BL/6 control mice or atherosclerotic mice; P = 0.0289, unpaired t test. Values shown are normalized to the mean of control animals. Each dot represents one animal: n = 5 control mice; n = 4 ApoE−/− and n = 4 LDLR−/− mice, pooled for this analysis (B) Primary biliary cirrhosis: Flow cytometric analysis of FoxP3 positive cells among CD4 positive cells in mice with induced PBC or control C57BL/6 mice. Hepatic lymph nodes; P = 0.0014, Mann–Whitney test. Each dot represents one animal: n = 7 and 8 animals, pooled from two independent PBC induction preparations. (C) Collagen Induced Arthritis. The ratio of Treg to total T cells, as indicated by the relative levels of FoxP3 to CD3ɛ mRNA measured by real-time qPCR analysis, in the joints of arthritic mice or mice that were protected from CIA-induced arthritis by becoming pregnant; P = 0.0028, Mann–Whitney test. Values shown are normalized to the mean of animals protected from arthritis. Each dot represents one animal: n = 7 and 5 animals, pooled from two independent CIA induction preparations.
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References

    1. Ait-Oufella H., Salomon B.L., Potteaux S., Robertson A.K., Gourdy P., Zoll J., Merval R., Esposito B., Cohen J.L., Fisson S., Flavell R.A., Hansson G.K., Klatzmann D., Tedgui A., Mallat Z. Natural regulatory T cells control the development of atherosclerosis in mice. Nat. Med. 2006;12:178–180. - PubMed
    1. Allan S.E., Broady R., Gregori S., Himmel M.E., Locke N., Roncarolo M.G., Bacchetta R., Levings M.K. CD4+ T-regulatory cells: toward therapy for human diseases. Immunol. Rev. 2008;223:391–421. - PubMed
    1. Ammirati E., Cianflone D., Vecchio V., Banfi M., Vermi A.C., De Metrio M., Grigore L., Pellegatta F., Pirillo A., Garlaschelli K., Manfredi A.A., Catapano A.L., Maseri A., Palini A.G., Norata G.D. Effector memory T cells are associated with atherosclerosis in humans and animal models. J. Am. Heart Assoc. 2012;1:27–41. - PMC - PubMed
    1. Benito-Miguel M., Garcia-Carmona Y., Balsa A., Perez de Ayala C., Cobo-Ibanez T., Martin-Mola E., Miranda-Carus M.E. A dual action of rheumatoid arthritis synovial fibroblast IL-15 expression on the equilibrium between CD4+CD25+ regulatory T cells and CD4+CD25− responder T cells. J. Immunol. 2009;183:8268–8279. - PubMed
    1. Chen G.Y., Chen C., Wang L., Chang X., Zheng P., Liu Y. Cutting edge: broad expression of the FoxP3 locus in epithelial cells: a caution against early interpretation of fatal inflammatory diseases following in vivo depletion of FoxP3-expressing cells. J. Immunol. 2008;180:5163–5166. - PMC - PubMed

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