Editorial How to Repeat a Success and Control a Bad Influence Goran K. Hansson, MD, PhD As a potentially dangerous defense system, the immune response is regulated by several sets of inhibitory cells and mol ecules. Foremost among them, regulatory T cells (Treg) dampen immune responses by inhibiting effector T-cell activity, B-cell and macrophage activation, and inflammatory responses. Several subtypes of Treg have been identified in the CD4 and CD8 T-cell families, with immunosuppressive activity mediated by the cyto kines interleukin-10 and transforming growth factor-|3.2 Complex regulatory loops allow for fine-tuning of the immune response in such a way that an invading pathogen can be eliminated with minimal damage to the host organism. A slight imbalance in the response to a low-intensity pathogen or to endogenous molecules, can lead to a chronic inflamma tory condition. Successful treatment of pathological immune responses has been achieved by interfering with immune cell activation or with effector cytokines that drive pathological inflammation. The first immunosuppressive drug, azathioprine, was dis covered by Gertrude Elion and George Hitchings, who were awarded the Nobel Prize in 1988. Azathioprine inhibits DNA synthesis that is required for the proliferation of activated B and T cells. It made organ transplantation between nonidenti cal humans possible and has been used to treat many autoim mune diseases. Further progress was made when the T cell-specific immu nosuppressants, cyclosporine, sirolimus, and tacrolimus, were identified. Their side effects are less significant than those of azathioprine, and they are used not only to prevent graft rejec tion, but also to treat a broad range of chronic inflammatory diseases, from autoimmune hepatitis to arterial restenosis. A second approach to immunotherapy is to eliminate T and B cells by using cytolytic antibodies. Monoclonal anti-CD20 antibodies that eliminate B cells have been particularly useful in the treatment of autoimmune diseases. A third major breakthrough was achieved by blocking the action of proinflammatory cytokines that mediate immunopathology. Tumor necrosis factor was known to be a major proinflammatory cytokine and Marc Feldmann identified it as a driving force in joint inflammation. Together with Ravinder Maini, he developed tumor necrosis factor blockade as a ther apy against rheumatoid arthritis, a strategy that has revolu tionized the treatment of this disease.3 Additional strategies involve blockade of interleukin-1, interleukin-6, and several other cytokines. All this progress in immunotherapy has had an enormous impact on transplantation, autoimmunity, and pathological inflammation. However, existing therapies all have potentially serious side effects and it would be desirable to have more subtle manipulations of the immune system at hand, particu larly for chronic inflammatory conditions that require long term treatment. Recent insights into immune regulation may offer possibilities for such treatment strategies.
he manipulation of adaptive immunity is probably the most successful preventive and therapeutic strategy of modem medicine. Its roots go back to Edward Jenner, who in 1796 induced immunity to smallpox by inoculation with the related cowpox vims.1 Although the mechanism of action remained completely unknown for more than a century, the concept of vaccination spread rapidly around the world and had an imme diate impact on population health. In Sweden, for instance, =20 000 people died of smallpox in 1800, just before the intro duction of vaccination. Within 20 years, the death rate had fallen to 200! The insightful bishop, Esaias Tegner, reported to the government that the population in his bishopric was increasing rapidly thanks to “peace, vaccine, and potatoes.” In 1980, the World Health Organization certified that small pox had been eradicated in the entire world. From Pasteur and onward, the vaccination principle was used to control many other diseases in addition to smallpox. Together with the sani tation of water and foodstuff, it represents the most successful means of disease prevention ever accomplished.
T
Article see p 560 Vaccination induces a T-cell response that helps B cells to react against antigen and start to produce high-affinity anti bodies. The T-cell response also leads to the development of armed effector T cells with the capacity to kill target cells such as infected ones, and to the activation of macrophages to promote inflammation. In this way, the T-cell response initi ates both humoral and cellular immunity to the immunogen. The relative importance of these 2 effector arms of adaptive immunity varies between vaccines, but the general principle operates in all vaccination protocols. The immune response elicited by vaccination mimics the one triggered by an invading pathogen. It also resembles the pathological immune responses observed in autoimmune con ditions and chronic inflammatory diseases. In these situations, autologous molecules are erroneously recognized as antigens. The ensuing immune response attacks tissues containing these molecules, leading to cell death, tissue destruction, and repair processes. Several immune effector systems contribute to these attacks, including cytotoxic T cells, complement-activating antibodies, phagocytizing macrophages, and other cells. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From Department of Medicine and Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. Correspondence to Goran K. Hansson, MD, PhD, Center for Molecular Medicine L8:03, Karolinska University Hospital L8:03, SE-17176 Stockholm, Sweden. E-mail [email protected] (Circulation. 2015;131:525-527. DOI: 10.1161/CIRCULATIONAHA.114.014560.) © 2014 American Heart Association. Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.114.014560
525
526
Circulation
February 10,2015
Atherosclerosis is a chronic inflammatory disease elicited when cholesterol-containing lipoproteins accumulate in the arterial intima.4,5 Its pathology involves macrophages, dif ferent sets of T cells, and antibodies to low-density lipopro teins.6,7 Whereas early immune activity is observed in intimal lesions, advanced atherosclerosis is accompanied by periadventitial formation of tertiary lymphoid structures resembling germinal centers of lymph nodes. Human atherosclerotic lesions contain both CD4+ and CD8+ T cells.4 In contrast, murine lesions are dominated by CD4+ T cells and nearly all mechanistic studies of the cellu lar immunology of atherosclerosis have focused on the CD4+ subtype. Similarly, most experimental research on humoral immunity in atherosclerosis has dealt with natural immuno globulin M antibodies produced by B 1 type B cells, although significant numbers of high-affinity immunoglobulin G (IgG) antibodies can also recognize low-density lipoprotein.8 The role of B cells in atherosclerosis is controversial. Transfer of spleen cell preparations containing both B l, mar ginal zone, and B2 cells protects against atherosclerosis,9 whereas antibody depletion data point to a proatherosclerotic role of B2 cells.10 Therefore, Bl cells were proposed to be atheroprotective, but B2 cells were assumed to exert a bad influence on atherosclerosis.8 The control of these disease regulating immune activities has remained unclear. In this issue of Circulation, Marc Clement, Antonino Nicoletti, and their coworkers" have elucidated an important regulatory loop that controls atherogenesis via B-cell modula tion. They unravel a sophisticated network for disease control in which mature B cells (B2) producing high-affinity IgG anti bodies are stimulated by help from antigen-specific T-helper follicular (Tfh) type CD4+ T cells. The latter are, in turn, con trolled by a negative signal from CD8+ Treg. Although B 1 cells make low-affinity natural antibodies con tinuously and as a direct response to antigen, the production of high-affinity IgG antibodies by B2 cells and plasma cells requires T-cell help. In this way, the T cell can control the ensu ing immune response by directing only certain antigen-specific B cells to divide, reorganize their immunoglobulin genes, and start producing high-affinity IgG antibodies to the antigen in question. The Tfh cell type is specialized in providing help for B cells.12 To perform this function, it is present in lymphoid follicles of secondary lymphoid organs, where B-cell differen tiation takes place. When follicular B cells react to antigen pre sented by follicular dendritic cells in the presence of Tfh cells, large amounts of high-affinity antibodies can be produced within a short period of time. This response plays a crucial role in host defense against many bacteria, virus, and toxins. If the stimulus persists, tertiary lymphoid structures are formed when Tfh and B cells migrate into inflamed organs and tissues such as the adventitia surrounding atherosclerotic lesions.13 If B cells start to produce high-affinity IgG antibodies that react to self-molecules, a potentially detrimental autoimmune situation arises. Therefore, Tfh cells are controlled by inhibi tory signals from CD8+ Treg.14 The latter cells depend for their activity on an major histocompatibility complex mol ecule called Qa-1 in the mouse and HLA-E in humans. Clement et al first observed that Tfh and mature, germinal center (GC)-type B cells expanded during atherosclerosis in
Apoe+ mice. They probed the Treg-Tfh axis by using a point mutation that abrogates the interaction between Qa-1 molecules on Tfh cells and the T-cell receptor on CD8+ Treg. In the absence of Treg-mediated inhibition, the Tfh population expanded fur ther, as did GC B cells. In the A/we-deficient mouse, athero sclerotic lesions were significantly increased in this situation, as were the size and number of adventitial tertiary lymphoid struc tures harboring IgG producing B cells and plasma cells. To confirm the critical role of the Treg-Tfh axis, the authors bypassed the defective Qa-1 molecules by ligating the induc ible costimulatory molecule that directly inhibits Tfh cells. This treatment reversed the phenotype of the Qa-1 mutation and normalized lesion size. Finally, the authors established that the Tfh-GC B-cell axis operates in human vascular disease. This was possible in patients who underwent surgery for abdominal aortic aneu rysms. During this procedure, the entire aortic wall is removed including the adventitia. In contrast, atherosclerotic lesions are usually treated by procedures that do not permit exami nation of the adventitial layer. Abdominal aortic aneurysm adventitia contained B-cell follicles with Tfh cells, similar to tertiary lymphoid organs of mice with advanced atheroscle rotic disease. Importantly, abdominal aortic aneurysm tissue released IgG molecules, indicating the production of these immunoglobulins by GC B cells and plasma cells, and also interleukin-21, a signature cytokine of Tfh cells. The take-home message of the Clement article" is that the Tfh-GC B-cell axis is proatherogenic, that it operates in adven titial tertiary lymphoid organs, that it is controlled by CD8+ Treg, and that it can be manipulated. Thus, interference with Treg-Tfh signaling increased atherosclerosis, whereas the direct delivery of an inhibitory signal to Tfh cells reduced it. The findings by the Nicoletti-Caligiuri laboratory may offer an opportunity to inhibit atherosclerosis by dampening the GC B-cell response. Will it result in benefit of the same magnitude as that achieved, for instance, by Feldmann and Maini3? This remains to be seen, and much more research will be needed before we know if the Treg-Tfh-GC B-cell axis contains ther apy targets suitable for attack in human atherosclerotic dis ease. The magnitude of the medical problem argues that this line of research should be pursued vigorously.
Acknowledgments The author's research is supported by the Swedish Research Council, Swedish Heart-Lung Foundation, Stockholm County Council, and the European Union.
Disclosures None.
References 1. Jenner E. An inquiry into the causes and effects of the variolae vaccinae, orcowpox. 1798. 2. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity. 2013;38:414-423. doi: 10.1016/j. immuni.2013.03.002. 3. Feldmann M, Maini RN. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoim mune diseases. Nat Med. 2003;9:1245-1250. doi: 10.1038/nm939.
Hansson
4. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685-1695. doi: 10.1056/NEJMra043430. 5. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317-325. doi: 10.1038/ naturel0146. 6. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12:204-212. doi: 10.1038/ni.2001. 7. Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms impli cated in atherosclerosis: from mice to humans. Immunity. 2013;38:10921104. doi: 10.1016/j.immuni.2013.06.009. 8. Tsiantoulas D, Diehl CJ, Witztum JL, Binder CJ. B cells and humoral immunity in atherosclerosis. Circ Res. 2014;114:1743-1756. doi: 10.1161/CIRCRESAHA.l 13.301145. 9. Caligiuri G, Nicoletti A, Poirier B, Hansson GK. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest. 2002;109:745-753. doi: 10.1172/JCI7272. 10. Ait-Oufella H, Herbin O. Bouaziz JD, Binder CJ, Uyttenhove C, Laurans L. Taleb S, Van Vre E, Esposito B, Vilar J, Sirvent J, Van Snick J, Tedgui A, Tedder TF, Mallat Z. B cell depletion reduces the development of atherosclerosis in mice. J Exp Med. 2010;207:1579-1587. doi: 10.1084/ jem.20100155.
B-Cell Control in Atherosclerosis
527
11. Clement M, Guedj K, Andreata F, Morvan M, Bey L, Khallou-Laschet J, Gaston A-T, Delbosc S, Alsac J-M, Bruneval P, Deschildre C, Le Borgne M, Castier Y, Kim H-J, Cantor H, Michel J-B, Caligiuri G, Nicoletti A. Control of the T follicular helper-germinal center B-cell axis by CD8+ regulatory T cells limits atherosclerosis and tertiary lymphoid organ devel opment. Circulation. 2015;131:560-570. 12. Tangye SG, Ma CS, Brink R, Deenick EK. The good, the bad and the ugly -TFH cells in human health and disease. Nat Rev Immunol. 2013;13:412— 426. doi: 10.1038/nri3447. 13. Grabner R, Lotzer K, Dopping S, Hildner M, Radke D, Beer M, Spanbroek R, Lippert B. Reardon CA, Getz GS, Fu YX, Hehlgans T, Mebius RE, van der Wall M, Kruspe D, Englert C, Lovas A, Hu D, Randolph GJ, Weill F, Habenicht AJ. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med. 2009;206:233-248. doi: I0.1084/jem.20080752. 14. Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature. 2010;467:328-332. doi: 10.1038/nature09370. Key W ords: Editorials ■ antibody affinity ■ atherosclerosis ■ B-lymphocytes
■ immune system ■ T-lymphocytes ■ therapeutics
Copyright of Circulation is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
he manipulation of adaptive immunity is probably the most successful preventive and therapeutic strategy of modem medicine. Its roots go back to Edward Jenner, who in 1796 induced immunity to smallpox by inoculation with the related cowpox vims.1 Although the mechanism of action remained completely unknown for more than a century, the concept of vaccination spread rapidly around the world and had an imme diate impact on population health. In Sweden, for instance, =20 000 people died of smallpox in 1800, just before the intro duction of vaccination. Within 20 years, the death rate had fallen to 200! The insightful bishop, Esaias Tegner, reported to the government that the population in his bishopric was increasing rapidly thanks to “peace, vaccine, and potatoes.” In 1980, the World Health Organization certified that small pox had been eradicated in the entire world. From Pasteur and onward, the vaccination principle was used to control many other diseases in addition to smallpox. Together with the sani tation of water and foodstuff, it represents the most successful means of disease prevention ever accomplished.
T
Article see p 560 Vaccination induces a T-cell response that helps B cells to react against antigen and start to produce high-affinity anti bodies. The T-cell response also leads to the development of armed effector T cells with the capacity to kill target cells such as infected ones, and to the activation of macrophages to promote inflammation. In this way, the T-cell response initi ates both humoral and cellular immunity to the immunogen. The relative importance of these 2 effector arms of adaptive immunity varies between vaccines, but the general principle operates in all vaccination protocols. The immune response elicited by vaccination mimics the one triggered by an invading pathogen. It also resembles the pathological immune responses observed in autoimmune con ditions and chronic inflammatory diseases. In these situations, autologous molecules are erroneously recognized as antigens. The ensuing immune response attacks tissues containing these molecules, leading to cell death, tissue destruction, and repair processes. Several immune effector systems contribute to these attacks, including cytotoxic T cells, complement-activating antibodies, phagocytizing macrophages, and other cells. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From Department of Medicine and Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. Correspondence to Goran K. Hansson, MD, PhD, Center for Molecular Medicine L8:03, Karolinska University Hospital L8:03, SE-17176 Stockholm, Sweden. E-mail [email protected] (Circulation. 2015;131:525-527. DOI: 10.1161/CIRCULATIONAHA.114.014560.) © 2014 American Heart Association. Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.114.014560
525
526
Circulation
February 10,2015
Atherosclerosis is a chronic inflammatory disease elicited when cholesterol-containing lipoproteins accumulate in the arterial intima.4,5 Its pathology involves macrophages, dif ferent sets of T cells, and antibodies to low-density lipopro teins.6,7 Whereas early immune activity is observed in intimal lesions, advanced atherosclerosis is accompanied by periadventitial formation of tertiary lymphoid structures resembling germinal centers of lymph nodes. Human atherosclerotic lesions contain both CD4+ and CD8+ T cells.4 In contrast, murine lesions are dominated by CD4+ T cells and nearly all mechanistic studies of the cellu lar immunology of atherosclerosis have focused on the CD4+ subtype. Similarly, most experimental research on humoral immunity in atherosclerosis has dealt with natural immuno globulin M antibodies produced by B 1 type B cells, although significant numbers of high-affinity immunoglobulin G (IgG) antibodies can also recognize low-density lipoprotein.8 The role of B cells in atherosclerosis is controversial. Transfer of spleen cell preparations containing both B l, mar ginal zone, and B2 cells protects against atherosclerosis,9 whereas antibody depletion data point to a proatherosclerotic role of B2 cells.10 Therefore, Bl cells were proposed to be atheroprotective, but B2 cells were assumed to exert a bad influence on atherosclerosis.8 The control of these disease regulating immune activities has remained unclear. In this issue of Circulation, Marc Clement, Antonino Nicoletti, and their coworkers" have elucidated an important regulatory loop that controls atherogenesis via B-cell modula tion. They unravel a sophisticated network for disease control in which mature B cells (B2) producing high-affinity IgG anti bodies are stimulated by help from antigen-specific T-helper follicular (Tfh) type CD4+ T cells. The latter are, in turn, con trolled by a negative signal from CD8+ Treg. Although B 1 cells make low-affinity natural antibodies con tinuously and as a direct response to antigen, the production of high-affinity IgG antibodies by B2 cells and plasma cells requires T-cell help. In this way, the T cell can control the ensu ing immune response by directing only certain antigen-specific B cells to divide, reorganize their immunoglobulin genes, and start producing high-affinity IgG antibodies to the antigen in question. The Tfh cell type is specialized in providing help for B cells.12 To perform this function, it is present in lymphoid follicles of secondary lymphoid organs, where B-cell differen tiation takes place. When follicular B cells react to antigen pre sented by follicular dendritic cells in the presence of Tfh cells, large amounts of high-affinity antibodies can be produced within a short period of time. This response plays a crucial role in host defense against many bacteria, virus, and toxins. If the stimulus persists, tertiary lymphoid structures are formed when Tfh and B cells migrate into inflamed organs and tissues such as the adventitia surrounding atherosclerotic lesions.13 If B cells start to produce high-affinity IgG antibodies that react to self-molecules, a potentially detrimental autoimmune situation arises. Therefore, Tfh cells are controlled by inhibi tory signals from CD8+ Treg.14 The latter cells depend for their activity on an major histocompatibility complex mol ecule called Qa-1 in the mouse and HLA-E in humans. Clement et al first observed that Tfh and mature, germinal center (GC)-type B cells expanded during atherosclerosis in
Apoe+ mice. They probed the Treg-Tfh axis by using a point mutation that abrogates the interaction between Qa-1 molecules on Tfh cells and the T-cell receptor on CD8+ Treg. In the absence of Treg-mediated inhibition, the Tfh population expanded fur ther, as did GC B cells. In the A/we-deficient mouse, athero sclerotic lesions were significantly increased in this situation, as were the size and number of adventitial tertiary lymphoid struc tures harboring IgG producing B cells and plasma cells. To confirm the critical role of the Treg-Tfh axis, the authors bypassed the defective Qa-1 molecules by ligating the induc ible costimulatory molecule that directly inhibits Tfh cells. This treatment reversed the phenotype of the Qa-1 mutation and normalized lesion size. Finally, the authors established that the Tfh-GC B-cell axis operates in human vascular disease. This was possible in patients who underwent surgery for abdominal aortic aneu rysms. During this procedure, the entire aortic wall is removed including the adventitia. In contrast, atherosclerotic lesions are usually treated by procedures that do not permit exami nation of the adventitial layer. Abdominal aortic aneurysm adventitia contained B-cell follicles with Tfh cells, similar to tertiary lymphoid organs of mice with advanced atheroscle rotic disease. Importantly, abdominal aortic aneurysm tissue released IgG molecules, indicating the production of these immunoglobulins by GC B cells and plasma cells, and also interleukin-21, a signature cytokine of Tfh cells. The take-home message of the Clement article" is that the Tfh-GC B-cell axis is proatherogenic, that it operates in adven titial tertiary lymphoid organs, that it is controlled by CD8+ Treg, and that it can be manipulated. Thus, interference with Treg-Tfh signaling increased atherosclerosis, whereas the direct delivery of an inhibitory signal to Tfh cells reduced it. The findings by the Nicoletti-Caligiuri laboratory may offer an opportunity to inhibit atherosclerosis by dampening the GC B-cell response. Will it result in benefit of the same magnitude as that achieved, for instance, by Feldmann and Maini3? This remains to be seen, and much more research will be needed before we know if the Treg-Tfh-GC B-cell axis contains ther apy targets suitable for attack in human atherosclerotic dis ease. The magnitude of the medical problem argues that this line of research should be pursued vigorously.
Acknowledgments The author's research is supported by the Swedish Research Council, Swedish Heart-Lung Foundation, Stockholm County Council, and the European Union.
Disclosures None.
References 1. Jenner E. An inquiry into the causes and effects of the variolae vaccinae, orcowpox. 1798. 2. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity. 2013;38:414-423. doi: 10.1016/j. immuni.2013.03.002. 3. Feldmann M, Maini RN. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoim mune diseases. Nat Med. 2003;9:1245-1250. doi: 10.1038/nm939.
Hansson
4. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685-1695. doi: 10.1056/NEJMra043430. 5. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317-325. doi: 10.1038/ naturel0146. 6. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12:204-212. doi: 10.1038/ni.2001. 7. Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms impli cated in atherosclerosis: from mice to humans. Immunity. 2013;38:10921104. doi: 10.1016/j.immuni.2013.06.009. 8. Tsiantoulas D, Diehl CJ, Witztum JL, Binder CJ. B cells and humoral immunity in atherosclerosis. Circ Res. 2014;114:1743-1756. doi: 10.1161/CIRCRESAHA.l 13.301145. 9. Caligiuri G, Nicoletti A, Poirier B, Hansson GK. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest. 2002;109:745-753. doi: 10.1172/JCI7272. 10. Ait-Oufella H, Herbin O. Bouaziz JD, Binder CJ, Uyttenhove C, Laurans L. Taleb S, Van Vre E, Esposito B, Vilar J, Sirvent J, Van Snick J, Tedgui A, Tedder TF, Mallat Z. B cell depletion reduces the development of atherosclerosis in mice. J Exp Med. 2010;207:1579-1587. doi: 10.1084/ jem.20100155.
B-Cell Control in Atherosclerosis
527
11. Clement M, Guedj K, Andreata F, Morvan M, Bey L, Khallou-Laschet J, Gaston A-T, Delbosc S, Alsac J-M, Bruneval P, Deschildre C, Le Borgne M, Castier Y, Kim H-J, Cantor H, Michel J-B, Caligiuri G, Nicoletti A. Control of the T follicular helper-germinal center B-cell axis by CD8+ regulatory T cells limits atherosclerosis and tertiary lymphoid organ devel opment. Circulation. 2015;131:560-570. 12. Tangye SG, Ma CS, Brink R, Deenick EK. The good, the bad and the ugly -TFH cells in human health and disease. Nat Rev Immunol. 2013;13:412— 426. doi: 10.1038/nri3447. 13. Grabner R, Lotzer K, Dopping S, Hildner M, Radke D, Beer M, Spanbroek R, Lippert B. Reardon CA, Getz GS, Fu YX, Hehlgans T, Mebius RE, van der Wall M, Kruspe D, Englert C, Lovas A, Hu D, Randolph GJ, Weill F, Habenicht AJ. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med. 2009;206:233-248. doi: I0.1084/jem.20080752. 14. Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature. 2010;467:328-332. doi: 10.1038/nature09370. Key W ords: Editorials ■ antibody affinity ■ atherosclerosis ■ B-lymphocytes
■ immune system ■ T-lymphocytes ■ therapeutics
Copyright of Circulation is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
