T-cell specificity and regulation in atherosclerosis (2015)

<p>Cardiovascular disease is the main cause of death in the world. The underlying cause in most cases is atherosclerosis, a chronic inflammatory disease. Subendothelial retention of lipoproteins triggers monocyte-derived macrophages and T-helper (Th) 1 cells to form lipid-laden atherosclerotic plaques in the artery wall. The Th1 cells react to autoantigens from the ApoB protein in low-density lipoprotein (LDL) perpetuating the inflammation initiated by the innate immune reactions to modified lipoproteins. Other T-helper cells are also active in the lesions with regulatory T cells (Treg) limiting the injurious inflammation, while the effects of Th17 cells are less clear.</p><p>The slow build-up of atherosclerotic plaques is asymptomatic, but eventually the plaque may cause symptoms. Plaque rupture or endothelial erosion induces thrombus formation that causes a heart attack or ischemic stroke. Advanced plaques usually contain large cholesterol-rich necrotic cores. This determines plaque stability along with a stable cap formation by smooth muscle cells and collagen. Prevention of risk factors has reduced mortality, but there is still a need for novel therapies to stabilize plaques and to treat arterial inflammation. The aim for this thesis is to investigate T-cell responses to LDL and regulation of Th cells during atherogenesis. Genetically modified mouse models were used to study LDL-reactive T cells, mechanisms involved in Th cell differentiation, and the subsequent influence on disease development.</p><p>Paper I shows how inflammatory signals from the atherosclerotic lesions contribute to Th17 cell differentiation by means of IL-6 and transforming growth factor β (TGF-β). Th17 cells produce IL-17A that promotes collagen synthesis by smooth muscle cells. This paper establishes a plaque-stabilizing role for Th17 cells and IL-17A, which is likely to operate in man and reduce incidence of myocardial infarctions.</p><p>Paper II establishes that Tregs have a protective role in atherosclerosis by modulating lipid metabolism. Depletion of Foxp3+ Tregs during atherogenesis impairs lipoprotein uptake by unleashing liver inflammation that downregulates the very low-density lipoprotein (VLDL)-regulating protein called sortilin. This leads to increased plasma cholesterol and development of large atherosclerotic plaques with lipid-filled necrotic cores.</p><p>Paper III shows how LDL-reactive T cells survive clonal selection in the thymus, differentiate into T follicular helper cells (Tfh), and promote a protective B-cell response with anti-LDL antibodies. These antibodies mediate lipoprotein clearance and lower plasma cholesterol, which protects against atherosclerosis.</p><p>All three papers presented in this thesis illustrate an intricate interplay between the immune system and lipoprotein metabolism, resulting in profound effects on atherosclerosis. These notions may lead to new therapies that stabilize atherosclerotic plaques through specific anti-inflammatory actions that are mirrored by lipid-lowering effects.</p><h3>List of scientific papers</h3><p>I. Gisterå A, Robertson AK, Andersson J, Ketelhuth DF, Ovchinnikova O, Nilsson SK, Lundberg AM, Li MO, Flavell RA, Hansson GK. Transforming growth factor-beta signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17-dependent pathway. Sci Transl Med. 2013; 5(196):196ra100. <br><a href="https://doi.org/10.1126/scitranslmed.3006133">https://doi.org/10.1126/scitranslmed.3006133</a><br><br> </p><p>II. Klingenberg R, Gerdes N, Badeau RM, Gisterå A, Strodthoff D, Ketelhuth DF, Lundberg AM, Rudling M, Nilsson SK, Olivecrona G, Zoller S, Lohmann C, Lüscher TF, Jauhiainen M, Sparwasser T, Hansson GK. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J Clin Invest. 2013; 123(3):1323-34. <br><a href="https://doi.org/10.1172/JCI63891">https://doi.org/10.1172/JCI63891</a><br><br> </p><p>III. Gisterå A, Klement MR, Mailer RK, Polyzos KA, Duhlin A, Karlsson MC, Ketelhuth DF, Hansson GK. LDL-reactive T cells protect against atherosclerosis by inducing lipid-lowering antibodies. [Manuscript]</p>