Download PDF
Thromb Haemost 2015; 114(04): 835-847
DOI: 10.1160/TH14-12-1084
Atherosclerosis and Ischaemic Disease
Schattauer GmbH

B regulatory cells are increased in hypercholesterolaemic mice and protect from lesion development via IL-10

Asa C. Strom   *
1   Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
,
Amanda J. Cross   *
1   Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
,
Jennifer E. Cole   *
1   Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
,
Paul A. Blair
2   Centre for Rheumatology Research, University College London, London, UK
,
Christoph Leib
1   Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
,
Michael E. Goddard
3   Experimental Medicine, University of Lund, Lund, Sweden
,
Elizabeth C. Rosser
2   Centre for Rheumatology Research, University College London, London, UK
,
Inhye Park
1   Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
,
Anna Hultgårdh Nilsson
3   Experimental Medicine, University of Lund, Lund, Sweden
,
Jan Nilsson
4   Clinical Sciences, Malmö University, Malmö, Sweden
,
Claudia Mauri   *
2   Centre for Rheumatology Research, University College London, London, UK
,
Claudia Monaco   *
1   Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
› Author Affiliations Financial support: European Commission (LSHM-CT-2006–037400-IMMUNATH, FP7-HEALTH-2007–2.4.2–1-AtheroRemo, and FP7-INNOVATION I HEALTH-F2–2013–602114-Athero-B-Cell), British Heart Foundation UK (PG/11/46/28979), and Kennedy Trust for Rheumatology Research.
Further Information

Publication History

Received: 24 December 2014

Accepted after major revision: 07 May 2015

Publication Date:
29 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Whilst innate B1-B cells are atheroprotective, adaptive B2-B cells are considered pro-atherogenic. Different subsets of B regulatory cells (Breg) have been described. In experimental arthritis and lupus-like disease, Breg are contained within the CD21hiCD23hiCD24hi B cell pool. The existence and role of Breg in vascular disease is not known. We sought to investigate the existence, identity and location of Breg in vascular disease. The representation of B2-B cell subsets in the spleens and lymph nodes (LNs) of Apolipoprotein E-/- (ApoE-/-) mice compared to controls was characterised by flow cytometry. Additionally, we utilised a model of neointima formation based on the placement of a perivascular collar around the carotid artery in ApoE-/- mice to ascertain whether B cells and B cell subsets confer protection against lesion development. Adoptive transfer of B cells was performed from wild type or genetically modified mice. We showed that CD21hiCD23hiCD24hi B cells are unexpectedly increased in the draining LNs of ApoE-/- mice. Adoptive transfer of LN-derived B2-B cells or purified CD21hiCD23hiCD24hi B cells to syngeneic mice reduced lesion size and inflammation without changing serum cholesterol levels. Follicular B2-B cells did not confer protection. IL-10 blockade or transfer of IL10-deficient B cells prevented LN-derived B cell-mediated protection. This is the first identification of a specific LN-derived B2-Breg subset that confers IL-10 mediated protection from neointima formation. This may open the way for immune modulatory approaches in cardiovascular disease.

Keywords

Immunity - B regulatory cells - interleukins - atherosclerosis - vascular disease

* The authors contributed equally to the paper.


 

  • References

  • 1 Buono C, Binder C, Stavrakis G. et al. T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proc Natl Acad Sci USA 2005; 102: 1596-1601.
    CrossrefPubMedSearch in Google Scholar
  • 2 Ait-Oufella H, Salomon BL, Potteaux S. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006; 12: 178-180.
    CrossrefPubMedSearch in Google Scholar
  • 3 Ait-Oufella H, Herbin O, Bouaziz JD. et al. B cell depletion reduces the development of atherosclerosis in mice. J Exp Med 2010; 207: 1579-1587.
    CrossrefPubMedSearch in Google Scholar
  • 4 Kyaw T, Tay C, Khan A. et al. Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis. J Immunol 2010; 185: 4410-4419.
    CrossrefPubMedSearch in Google Scholar
  • 5 Sasaki Y, Casola S, Kutok JL. et al. TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology. J Immunol 2004; 173: 2245-2252.
    CrossrefPubMedSearch in Google Scholar
  • 6 Kyaw T, Tay C, Hosseini H. et al. Depletion of B2 but not B1a B cells in BAFF receptor-deficient ApoE mice attenuates atherosclerosis by potently ameliorating arterial inflammation. PloS one 2012; 7: e29371.
    CrossrefPubMedSearch in Google Scholar
  • 7 Sage AP, Tsiantoulas D, Baker L. et al. BAFF receptor deficiency reduces the development of atherosclerosis in mice--brief report. Arterioscler Thromb Vasc Biol 2012; 32: 1573-1576.
    CrossrefPubMedSearch in Google Scholar
  • 8 Kyaw T, Cui P, Tay C. et al. BAFF receptor mAb treatment ameliorates development and progression of atherosclerosis in hyperlipidemic ApoE(-/-) mice. PloS one 2013; 8: e60430.
    CrossrefPubMedSearch in Google Scholar
  • 9 Major A, Fazio S, Linton M. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler Thromb Vasc Biol 2002; 22: 1892-1898.
    CrossrefPubMedSearch in Google Scholar
  • 10 Caligiuri G, Nicoletti A, Poirier B. et al. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest 2002; 109: 745-753.
    CrossrefPubMedSearch in Google Scholar
  • 11 Doran AC, Lipinski MJ, Oldham SN. et al. B-cell aortic homing and atheroprotection depend on Id3. Circ Res 2012; 110: e1-12.
    CrossrefPubMedSearch in Google Scholar
  • 12 Gjurich BN, Taghavie-Moghadam PL, Ley K. et al. L-selectin deficiency decreases aortic B1a and Breg subsets and promotes atherosclerosis. Thromb Hae-most 2014; 112: 803-811.
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Dimayuga P, Cercek B, Oguchi S. et al. Inhibitory effect on arterial injury-induced neointimal formation by adoptive B-cell transfer in Rag-1 knockout mice. Arterioscler Thromb Vasc Biol 2002; 22: 644-649.
    CrossrefPubMedSearch in Google Scholar
  • 14 Hayakawa K, Hardy RR, Herzenberg LA. et al. Progenitors for Ly-1 B cells are distinct from progenitors for other B cells. J Exp Med 1985; 161: 1554-1568.
    CrossrefPubMedSearch in Google Scholar
  • 15 Kyaw T, Tay C, Krishnamurthi S. et al. B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions. Circ Res 2011; 109: 830-840.
    CrossrefPubMedSearch in Google Scholar
  • 16 Shaw PX, Hörkkö S, Chang MK. et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest 2000; 105: 1731-1740.
    CrossrefPubMedSearch in Google Scholar
  • 17 Lewis MJ, Malik TH, Ehrenstein MR. et al. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 2009; 120: 417-426.
    CrossrefPubMedSearch in Google Scholar
  • 18 Mauri C, Gray D, Mushtaq N. et al. Prevention of arthritis by interleukin 10-producing B cells. J Exp Med 2003; 197: 489-501.
    CrossrefPubMedSearch in Google Scholar
  • 19 Evans JG, Chavez-Rueda KA, Eddaoudi A. et al. Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol 2007; 178: 7868-7878.
    CrossrefPubMedSearch in Google Scholar
  • 20 Matsushita T, Yanaba K, Bouaziz J-D. et al. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest 2008; 118: 3420-3430.
    PubMedSearch in Google Scholar
  • 21 Rosser EC, Oleinika K, Tonon S. et al. Regulatory B cells are induced by gut microbiota-driven interleukin-1beta and interleukin-6 production. Nat Med 2014; 20: 1334-1339.
    CrossrefPubMedSearch in Google Scholar
  • 22 Chyu KY, Dimayuga P, Zhu J. et al. Decreased neointimal thickening after arterial wall injury in inducible nitric oxide synthase knockout mice. Circ Res 1999; 85: 1192-1198.
    CrossrefPubMedSearch in Google Scholar
  • 23 Asseman C, Mauze S, Leach MW. et al. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999; 190: 995-1004.
    CrossrefPubMedSearch in Google Scholar
  • 24 Cole JE, Navin TJ, Cross AJ. et al. Unexpected protective role for Toll-like receptor 3 in the arterial wall. Proc Natl Acad Sci USA 2011; 108: 2372-2377.
    CrossrefPubMedSearch in Google Scholar
  • 25 Meyer-Bahlburg A, Andrews SF, Yu KO. et al. Characterisation of a late transitional B cell population highly sensitive to BAFF-mediated homeostatic proliferation. J Exp Med 2008; 205: 155-168.
    CrossrefPubMedSearch in Google Scholar
  • 26 Blair PA, Chavez-Rueda KA, Evans JG. et al. Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice. J Immunol 2009; 182: 3492-3502.
    CrossrefPubMedSearch in Google Scholar
  • 27 Angeli V, Llodrá J, Rong JX. et al. Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilisation. Immunity 2004; 21: 561-574.
    CrossrefPubMedSearch in Google Scholar
  • 28 Binder CJ, Hartvigsen K, Chang M-K. et al. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J Clin Invest 2004; 114: 427-437.
    CrossrefPubMedSearch in Google Scholar
  • 29 Mizoguchi A, Mizoguchi E, Takedatsu H. et al. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 2002; 16: 219-230.
    CrossrefPubMedSearch in Google Scholar
  • 30 Srivastava B, Quinn 3rd WJ, Hazard K. et al. Characterisation of marginal zone B cell precursors. J Exp Med 2005; 202: 1225-1234.
    CrossrefPubMedSearch in Google Scholar
  • 31 Grammer AC, Bergman MC, Miura Y. et al. The CD40 ligand expressed by human B cells costimulates B cell responses. J Immunol 1995; 154: 4996-5010.
    PubMedSearch in Google Scholar
  • 32 Mallat Z, Besnard S, Duriez M. et al. Protective role of interleukin-10 in atherosclerosis. Circ Res 1999; 85: e17-24.
    CrossrefPubMedSearch in Google Scholar
  • 33 Caligiuri G, Rudling M, Ollivier V. et al. Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol Med 2003; 9: 10-17.
    PubMedSearch in Google Scholar
  • 34 Zimmerman MA, Reznikov LL, Raeburn CD. et al. Interleukin-10 attenuates the response to vascular injury. J Surg Res 2004; 121: 206-213.
    CrossrefPubMedSearch in Google Scholar
  • 35 Mazighi M. IL-10 inhibits vascular smooth muscle cell activation in vitro and in vivo. Am J Physiol Heart Circ Physiol 2004; 287: H866-H871.
    CrossrefPubMedSearch in Google Scholar
  • 36 Eefting D, Schepers A, De Vries MR. et al. The effect of interleukin-10 knockout and overexpression on neointima formation in hypercholesterolemic APOE*3-Leiden mice. Atherosclerosis 2007; 193: 335-342.
    CrossrefPubMedSearch in Google Scholar
  • 37 Mauri C, Bosma A. Immune Regulatory Function of B Cells. Ann Rev Immunol. 2012 30. null.
    PubMedSearch in Google Scholar
  • 38 Mallat Z, Gojova A, Brun V. et al. Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice. Circulation 2003; 108: 1232-1237.
    CrossrefPubMedSearch in Google Scholar
  • 39 Lipinski MJ, Perry HM, Doran AC. et al. Comment on “Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis”. J Immunol. 2011 186. 4; author reply 6.
    PubMedSearch in Google Scholar
  • 40 Pillai S, Cariappa A. The follicular versus marginal zone B lymphocyte cell fate decision. Nat Rev Immunol 2009; 9: 767-777.
    CrossrefPubMedSearch in Google Scholar
  • 41 Yoshizaki A, Miyagaki T, DiLillo DJ. et al. Regulatory B cells control T-cell auto-immunity through IL-21-dependent cognate interactions. Nature 2012; 491: 264-268.
    CrossrefPubMedSearch in Google Scholar
  • 42 Blair PA, Noreña LY, Flores-Borja F. et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity 2010; 32: 129-140.
    CrossrefPubMedSearch in Google Scholar