Clément Cochain1, Miriam Koch1, Sweena M Chaudhari1, Martin Busch1, Jaroslav Pelisek1, Louis Boon1, Alma Zernecke2. 1. From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (C.C., M.K., S.M.C., A.Z.) and Rudolf Virchow Center (M.B.), University of Würzburg, Würzburg, Germany; Department of Vascular Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany (J.P.); and Bioceros, Utrecht, The Netherlands (L.B.). 2. From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (C.C., M.K., S.M.C., A.Z.) and Rudolf Virchow Center (M.B.), University of Würzburg, Würzburg, Germany; Department of Vascular Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany (J.P.); and Bioceros, Utrecht, The Netherlands (L.B.). alma.zernecke@uni-wuerzburg.de.
Abstract
RATIONALE: Proinflammatory adaptive immune responses are recognized as major drivers of atherosclerotic lesion formation. Although CD8(+) T cells have recently been proposed as a proatherogenic cell subset, their full scope of actions remains to be elucidated. OBJECTIVE: We here addressed the contribution of CD8(+) T cells to monocyte trafficking in atherosclerosis. METHOD AND RESULTS: We observed that CD8(+) T cells express proinflammatory cytokines (interferon-γ, tumor necrosis factor-α, and interleukin-12) within atherosclerotic lesions and spleens of high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. Antibody-mediated CD8(+) T-cell depletion in high-fat diet-fed Ldlr(-/-) mice decreased atherosclerotic plaque formation, associated with decreased macrophage accumulation within lesions. Despite a reduction in vascular chemokine (CC-motif) ligand 2 and chemokine (CXC-motif) ligand 1 expression, CD8(+) T-cell depletion did not directly affect monocyte recruitment to inflamed vessels. However, CD8(+) T-cell depletion decreased chemokine (CC-motif) ligand serum concentrations and circulating Ly6C(high) monocyte counts. We further evidenced that CD8(+) T-cell depletion decreased levels of mature monocytes and myeloid granulocyte-monocyte progenitors in the bone marrow and spleen of hypercholesterolemic mice, effects that were partially reproduced by interferon-γ neutralization, showing a role for interferon-γ. CONCLUSIONS: These data suggest that CD8(+) T cells promote atherosclerosis by controlling monopoiesis and circulating monocyte levels, which ultimately contributes to plaque macrophage burden without affecting direct monocyte recruitment, identifying this cell subset as a critical regulator of proatherogenic innate immune cell responses in atherosclerosis.
RATIONALE: Proinflammatory adaptive immune responses are recognized as major drivers of atherosclerotic lesion formation. Although CD8(+) T cells have recently been proposed as a proatherogenic cell subset, their full scope of actions remains to be elucidated. OBJECTIVE: We here addressed the contribution of CD8(+) T cells to monocyte trafficking in atherosclerosis. METHOD AND RESULTS: We observed that CD8(+) T cells express proinflammatory cytokines (interferon-γ, tumor necrosis factor-α, and interleukin-12) within atherosclerotic lesions and spleens of high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. Antibody-mediated CD8(+) T-cell depletion in high-fat diet-fed Ldlr(-/-) mice decreased atherosclerotic plaque formation, associated with decreased macrophage accumulation within lesions. Despite a reduction in vascular chemokine (CC-motif) ligand 2 and chemokine (CXC-motif) ligand 1 expression, CD8(+) T-cell depletion did not directly affect monocyte recruitment to inflamed vessels. However, CD8(+) T-cell depletion decreased chemokine (CC-motif) ligand serum concentrations and circulating Ly6C(high) monocyte counts. We further evidenced that CD8(+) T-cell depletion decreased levels of mature monocytes and myeloid granulocyte-monocyte progenitors in the bone marrow and spleen of hypercholesterolemic mice, effects that were partially reproduced by interferon-γ neutralization, showing a role for interferon-γ. CONCLUSIONS: These data suggest that CD8(+) T cells promote atherosclerosis by controlling monopoiesis and circulating monocyte levels, which ultimately contributes to plaque macrophage burden without affecting direct monocyte recruitment, identifying this cell subset as a critical regulator of proatherogenic innate immune cell responses in atherosclerosis.
Authors: Denitra A Breuer; Maria Cristina Pacheco; M Kay Washington; Stephanie A Montgomery; Alyssa H Hasty; Arion J Kennedy Journal: Am J Physiol Gastrointest Liver Physiol Date: 2019-11-11 Impact factor: 4.052
Authors: Alma Zernecke; Holger Winkels; Clément Cochain; Jesse W Williams; Dennis Wolf; Oliver Soehnlein; Clint S Robbins; Claudia Monaco; Inhye Park; Coleen A McNamara; Christoph J Binder; Myron I Cybulsky; Corey A Scipione; Catherine C Hedrick; Elena V Galkina; Tin Kyaw; Yanal Ghosheh; Huy Q Dinh; Klaus Ley Journal: Circ Res Date: 2020-07-16 Impact factor: 17.367