title: Control of the T follicular helper-germinal center B-cell axis by CD8⁺ regulatory T cells limits atherosclerosis and tertiary lymphoid organ development.
abstract: BACKGROUND
  The atheromodulating activity of B cells during the development of atherosclerosis is well documented, but the mechanisms by which these cells are regulated have not been investigated.
  
  
  RESULTS
  Here, we analyzed the contribution of Qa-1-restricted CD8(+) regulatory T cells to the control of the T follicular helper-germinal center B-cell axis during atherogenesis. Genetic disruption of CD8(+) regulatory T cell function in atherosclerosis-prone apolipoprotein E knockout mice resulted in overactivation of this axis in secondary lymphoid organs, led to the increased development of tertiary lymphoid organs in the aorta, and enhanced disease development. In contrast, restoring control of the T follicular helper-germinal center B-cell axis by blocking the ICOS-ICOSL pathway reduced the development of atherosclerosis and the formation of tertiary lymphoid organs. Moreover, analyses of human atherosclerotic aneurysmal arteries by flow cytometry, gene expression analysis, and immunofluorescence confirmed the presence of T follicular helper cells within tertiary lymphoid organs.
  
  
  CONCLUSIONS
  This study is the first to demonstrate that the T follicular helper-germinal center B-cell axis is proatherogenic and that CD8(+) regulatory T cells control the germinal center reaction in both secondary and tertiary lymphoid organs. Therefore, disrupting this axis represents an innovative therapeutic approach.
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Marc
authors.initials: M
authors.lastname: Clement
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Kevin
authors.initials: K
authors.lastname: Guedj
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreata
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Marion
authors.initials: M
authors.lastname: Morvan
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Laetitia
authors.initials: L
authors.lastname: Bey
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Jamila
authors.initials: J
authors.lastname: Khallou-Laschet
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Anh-Thu
authors.initials: AT
authors.lastname: Gaston
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delbosc
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Alsac
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Catherine
authors.initials: C
authors.lastname: Deschildre
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Marie
authors.initials: M
authors.lastname: Le Borgne
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Yves
authors.initials: Y
authors.lastname: Castier
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Harvey
authors.initials: H
authors.lastname: Cantor
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.).
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Caligiuri
authors.affiliation: From Unité 1148, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital X Bichat, Paris, France (M.C., K.G., F.A., M.M., J.-.K.L., A.-T.G., S.D., C.D., M.L.B., Y.C., J.-B.M., G.C., A.N.); Université Denis Diderot, Paris VII, Paris, France (M.C., K.G., F.A., L.B., J.-K.L., M.L.B., A.N.); Hôpital Européen Georges Pompidou, AP-HP, Faculté de Médecine René Descartes, Université Paris 5, Paris, France (J.-M.A., P.B.); and Department of Pathology, Harvard Medical School, Boston, MA (H.-J.K., H.C.). antonino.nicoletti@inserm.fr.
authors.forename: Antonino
authors.initials: A
authors.lastname: Nicoletti
mesh_terms: D063194:Adventitia / Q000276:immunology / Q000473:pathology; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory
chemical_list: C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand
keywords: atherosclerosis; inflammation; leukocytes