Marc Clement1, Kevin Guedj1, Francesco Andreata1, Marion Morvan1, Laetitia Bey1, Jamila Khallou-Laschet1, Anh-Thu Gaston1, Sandrine Delbosc1, Jean-Marc Alsac1, Patrick Bruneval1, Catherine Deschildre1, Marie Le Borgne1, Yves Castier1, Hye-Jung Kim1, Harvey Cantor1, Jean-Baptiste Michel1, Giuseppina Caligiuri1, Antonino Nicoletti2. 1. 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.). 2. 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.
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. METHODS AND 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.
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. METHODS AND 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 humanatherosclerotic 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: Benjamin Dallaudiere; Liliane Louedec; Marie Paule Jacob Lenet; Lionel Pesquer; Elvind Blaise; Anne Perozziello; Jean Baptiste Michel; Maryse Moinard; Philippe Meyer; Jean Michel Serfaty Journal: Muscles Ligaments Tendons J Date: 2015-07-03
Authors: Parésa L Taghavie-Moghadam; Tayab C Waseem; Julian Hattler; Lindsey M Glenn; Anca D Dobrian; Mark H Kaplan; Yi Yang; Roza Nurieva; Jerry L Nadler; Elena V Galkina Journal: J Immunol Date: 2017-10-20 Impact factor: 5.422