- Email: [email protected]
A Local Role for CD103+ Dendritic Cells in Atherosclerosis
Immunity
Previews stimulated in vitro. The model used by Cui et al. deliberately limited deletion of STAT3 to activated T cells; hence they were not in a position to address a role for the factor in the naive pool—but this is fertile ground for new studies in mice. Together, these complementary studies in mice and humans establish an important role for STAT3 in memory T cell formation and suggest that cytokines such as IL-10 and IL-21 may be critical in dictating whether activated T cells will divert to the effector population or join the ranks of the functional memory T cell pool.
REFERENCES
Harty, J.T., and Badovinac, V.P. (2008). Nat. Rev. Immunol. 8, 107–119.
Banerjee, A., Gordon, S.M., Intlekofer, A.M., Paley, M.A., Mooney, E.C., Lindsten, T., Wherry, E.J., and Reiner, S.L. (2010). J. Immunol. 185, 4988–4992.
Ichii, H., Sakamoto, A., Kuroda, Y., and Tokuhisa, T. (2004). J. Immunol. 173, 883–891.
Castellino, F., and Germain, R.N. (2007). J. Immunol. 178, 778–787. Cui, W., and Kaech, S.M. (2010). Immunol. Rev. 236, 151–166. Cui, W., Liu, Y., Weinstein, J.S., Craft, J., and Kaech, S.M. (2011). Immunity 35, this issue, 792–805. Foulds, K.E., Rotte, M.J., and Seder, R.A. (2006). J. Immunol. 177, 2565–2574.
Rutishauser, R.L., Martins, G.A., Kalachikov, S., Chandele, A., Parish, I.A., Meffre, E., Jacob, J., Calame, K., and Kaech, S.M. (2009). Immunity 31, 296–308. Siegel, A.M., Heimall, J., Freeman, A.F., Hsu, A.P., Brittain, E., Brenchley, J.M., Douek, D.C., Fahle, G.H., Cohen, J.I., Holland, S.M., and Milner, J.D. (2011). Immunity 35, this issue, 806–818. Yi, J.S., Ingram, J.T., and Zajac, A.J. (2010). J. Immunol. 185, 4835–4845. Yoshimura, A., Naka, T., and Kubo, M. (2007). Nat. Rev. Immunol. 7, 454–465.
A Local Role for CD103+ Dendritic Cells in Atherosclerosis Sammy Bedoui1 and William R. Heath1,* 1Department of Microbiology & Immunology, The University of Melbourne, Parkville 3010, Victoria, Australia *Correspondence: [email protected] DOI 10.1016/j.immuni.2011.11.005
In this issue of Immunity, Choi et al. (2011) analyzed the cellular composition of aortic vessels in normal and atherosclerotic mice, revealing the presence of conventional CD103+ DCs with a potentially protective influence on atherosclerosis. Atherosclerosis with its typical complications of stroke and heart attack continues to be the primary cause of death in westernized societies. In this issue of Immunity, Steinman and colleagues explore the cellular composition of normal and atherosclerotic aortic tissue, confirming the presence of macrophages and dendritic cells (DCs) of monocyte origin but also revealing the presence of a CD103+ DC subset that is developmentally dependent on FMS-like tyrosine kinase 3 receptor ligand (Flt3L) and is of nonmonocyte origin (Figure 1). Association of this DC population with atherosclerotic tissues appears to be protective and correlates with a relative increase in regulatory T (Treg) cells. A simplified view of atherosclerosis envisages a sequential model (Libby et al., 2011), whereby hemodynamic forces impacting on distinct areas of the vasculature, such as the lesser curvature of the
aortic arch, result in qualitative changes to endothelial cells lining these vessels. Changes include upregulation of adhesion molecules through which circulating monocytes gain access to the intima, an area of connective tissue located immediately below the basement membrane of the endothelium (Figure 1). Endothelial dysfunction also affects vessel wall permeability, promoting uptake and retention of circulating lipids, such as cholesterol-containing low-density lipoproteins (LDLs). These fatty particles are engulfed by monocyte-derived macrophages that eventually become engorged to histologically appear as ‘‘foam cells’’ (Lusis, 2000). The crystalline nature of some of these deposits not only makes their elimination by macrophages difficult, but also evokes inflammasome activation and the secretion of proinflammatory cytokines. The consequence of this inflammatory response is swelling of the intimal space,
perpetuation of endothelial dysfunction, further recruitment of leukocytes, and exacerbation of hemodynamic stress due to bulging of the lesion into the vessel lumen. When the endothelial lining eventually ruptures, platelet activation and thrombus formation lead to the characteristic atherosclerotic lesions that can either occlude the vessel lumen locally or, upon dislodgement, block distant arteries. Atherosclerosis is not only a critical medical concern, but represents an interesting disease for immunologists to study basic mechanisms of localized inflammation. Although atherosclerosis is associated with intimal immigration of a variety of leukocytes, including monocytes, DCs, T cells, B cells, and mast cells, it is widely believed that monocytederived macrophages are the dominant phagocytic cell type involved in the pathogenesis of this disease. Building
Immunity 35, November 23, 2011 ª2011 Elsevier Inc. 665
Immunity
Previews
Figure 1. Diagram of Aortic Regions with a Schematic Cross-section of the Vessel Wall Showing Developing Atherosclerosis The intima is infiltrated by monocyte-derived macrophages (CD11clo CD11b+ F4/80+ MHClo), some of which develop into foam cells upon accumulation of modified low density lipoproteins. The intima also contains monocyte-derived dendritic cells (CD11chi MHChi CD11b+ F4/80+) and a population of Flt3-dependent dendritic cells (CD11chi MHChi CD11b CD103+) that are not of monocyte origin. This latter population appears to be atheroprotective, possibly through their ability to interact with Treg cells.
on earlier work (Choi et al., 2009; Weber et al., 2008), Steinman and colleagues observed that aortic tissues contained a substantial proportion of cells with a DC phenotype (CD11chi MHC IIhi) (Figure 1). To ensure that these cells were indeed DCs, they performed a series of experiments. Combining flow cytometry and
immunofluorescence, they observed that CD11chi MHC IIhi cells increased in mice treated with the DC growth factor Flt3L, whereas the number of CD11clo F4/80+ cells remained unchanged. The latter cells were then revealed to be macrophages, given that they displayed excellent phagocytic activities, although
666 Immunity 35, November 23, 2011 ª2011 Elsevier Inc.
their ability to stimulate naive CD4+ and CD8+ T cells was poor. Conversely, CD11chi MHC IIhi cells took up beads poorly, but were efficient stimulators of T cells. Together with the selective absence of CD11clo F4/80+ cells in mice lacking macrophage colony stimulating factor, these findings show that the mouse aortic tissues examined here contained populations of macrophages (CD11clo F4/80+) and DCs (CD11chi MHC IIhi). Thus, whereas previous studies had reported the presence of cells with DC-like characteristics in vessel tissues, the present study defines what constitutes a macrophage and a DC in vessel tissues by using developmental and functional distinctions. It had been assumed that DCs found in aortic tissues were only of the inflammatory type that differentiates in situ from monocytes (Weber et al., 2008). The author’s first clue that this might not necessarily be the case came from immunohistology showing that not all CD11chi MHC IIhi cells coexpressed CD11b. Flow cytometry subsequently revealed that the aortic tissues contained two distinct types of DCs: one characterized by expression of high amounts of CD11b and F4/80 (CD11b+ DC) and another expressing low amounts of CD11b, but staining positive for the integrin CD103 (CD103+ DCs). This observation aligns very well with the DC subset composition of other peripheral organs, such as the skin or lungs, in which a distinct CD11b+ DC subset can be separated from CD103+ DCs (Heath and Carbone, 2009). Consistent with their disparate developmental origins, Steinman and colleagues found that CD103+ DCs were selectively increased in the presence of Flt3L and absent from aortic tissues of Flt3 / mice. In contrast, CD11b+ DCs were implicated to arise from monocytes through a series of experiments involving CD11b-DTR mice, Csf1 / mice, and in vivo labeling studies with an antibody against DC-SIGN. Thus, a key finding from this work is that the aortic intima contains conventional DCs that differentiate from Flt3-dependent precursors, rather than monocytes, in addition to the previously described monocyte-derived DCs. Importantly, Choi et al. (2011) find that the presence of Flt3-dependent CD103+ DCs is inversely correlated with aortic
Immunity
Previews lesions size, suggesting an atheroprotective role for this DC subset. On the basis of a relative increase in regulatory T cells within lesions, reduced tissue expression of mRNA for proinflammatory cytokines, and previous reports of atheroprotective effects of Treg cells (Ait-Oufella et al., 2006), the authors suggest that the protective role of CD103+ DC relates to their ability to regulate local Treg cell homeostasis. Although such a conclusion is consistent with reports of Treg cell stimulation by CD103+ DCs in the intestine (Coombes et al., 2007), these latter DCs express CD11b (Edelson et al., 2010) and are probably distinct from those in the aortic tissue. An important control experiment for these findings in Flt3 / mice was that plasma lipid profiles were not different relative to control mice, as at least some of the DCs that are missing in these mice could act as sinks for oxidized LDLs through their selective expression of the translocase CD36. One of the intriguing aspects of this study relates to the distribution of the different DC subsets throughout different anatomical parts of the ‘‘normal’’ aorta. The aortic sinus, which describes a widening of the aortic diameter at its origin at the heart, had more CD103+ DCs relative to CD11b+ DCs when compared to other areas such as the thoracic aorta. In this respect, it is also interesting to note that the increase in Flt3-sensitive DCs (CD103+ DCs) was very prominent at the opening of an arterial branch. This uneven distribution pattern between the two DC subsets in aortic tissues correlates nicely with the typical distribution pattern of atherosclerotic lesions, which develop predominantly at sites subjected
to strong hemodynamic forces, such as the aortic sinus, the lesser curvature of the aorta or branch points of smaller vessels. Although lesion development is much more accentuated in mouse models of atherosclerosis, atherosclerotic lesions also develop in normal mice and healthy humans. Immediate precursors to atherosclerotic lesions (‘‘fatty streaks’’) can be found in the aorta of healthy humans as early as in the first decade of life (Libby et al., 2011). It is therefore possible that the ‘‘normal’’ B6 mice utilized to analyze the distribution pattern of the DCs already had atherosclerotic lesions in these predilection spots and that the relative dominance of CD103+ DCs over CD11b+ DCs in these areas was a consequence of developing disease. The demonstration of elevated numbers of Flt3-dependent CD103+ DCs in atherosclerotic lesions of Ldlr / mice fed a high-fat diet further supports this view. It will be important to examine the causal relationship between this increase and the development of atherosclerotic lesions. Because CD103+ DCs usually reside in the tissues and upon maturation migrate via afferent lymphatics into the local draining lymph node (Heath and Carbone, 2009), it will also be interesting to examine whether CD103+ DCs migrate from the intima to draining LN. Whereas this study by Steinman and colleagues implicates CD103+ DCs in an atheroprotective role, it did not specifically address how monocyte-derived DCs contributed to atherosclerosis development. However, a very recent study shows that a type of CD11b+ DC characterized by the production of CCL17 appears to promote atheroscle-
rosis development and to inhibit Treg cell responses (Weber et al., 2011), raising the possibility that local Treg cell responses during atherosclerosis are regulated through a balance between inhibitory effects by monocyte-derived DCs and activating signals exerted by CD103+ DCs. Clearly more work is required to delineate precisely how these distinct types of DC impact on atherosclerosis development. REFERENCES Ait-Oufella, H., Salomon, B.L., Potteaux, S., Robertson, A.K., Gourdy, P., Zoll, J., Merval, R., Esposito, B., Cohen, J.L., Fisson, S., et al. (2006). Nat. Med. 12, 178–180. Choi, J.H., Do, Y., Cheong, C., Koh, H., Boscardin, S.B., Oh, Y.S., Bozzacco, L., Trumpfheller, C., Park, C.G., and Steinman, R.M. (2009). J. Exp. Med. 206, 497–505. Choi, J.H., Cheong, C., Dandamudi, D.B., Park, C.G., Rodriguez, A., Mehandru, S., Velinzon, K., and Jung, I. (2011). Immunity 35, this issue, 819–831. Coombes, J.L., Siddiqui, K.R., Arancibia-Ca´rcamo, C.V., Hall, J., Sun, C.M., Belkaid, Y., and Powrie, F. (2007). J. Exp. Med. 204, 1757–1764. Edelson, B.T., Kc, W., Juang, R., Kohyama, M., Benoit, L.A., Klekotka, P.A., Moon, C., Albring, J.C., Ise, W., Michael, D.G., et al. (2010). J. Exp. Med. 207, 823–836. Heath, W.R., and Carbone, F.R. (2009). Nat. Immunol. 10, 1237–1244. Libby, P., Ridker, P.M., and Hansson, G.K. (2011). Nature 473, 317–325. Lusis, A.J. (2000). Nature 407, 233–241. Weber, C., Zernecke, A., and Libby, P. (2008). Nat. Rev. Immunol. 8, 802–815. Weber, C., Meiler, S., Do¨ring, Y., Koch, M., Drechsler, M., Megens, R.T., Rowinska, Z., Bidzhekov, K., Fecher, C., Ribechini, E., et al. (2011). J. Clin. Invest. 121, 2898–2910.
Immunity 35, November 23, 2011 ª2011 Elsevier Inc. 667
Previews stimulated in vitro. The model used by Cui et al. deliberately limited deletion of STAT3 to activated T cells; hence they were not in a position to address a role for the factor in the naive pool—but this is fertile ground for new studies in mice. Together, these complementary studies in mice and humans establish an important role for STAT3 in memory T cell formation and suggest that cytokines such as IL-10 and IL-21 may be critical in dictating whether activated T cells will divert to the effector population or join the ranks of the functional memory T cell pool.
REFERENCES
Harty, J.T., and Badovinac, V.P. (2008). Nat. Rev. Immunol. 8, 107–119.
Banerjee, A., Gordon, S.M., Intlekofer, A.M., Paley, M.A., Mooney, E.C., Lindsten, T., Wherry, E.J., and Reiner, S.L. (2010). J. Immunol. 185, 4988–4992.
Ichii, H., Sakamoto, A., Kuroda, Y., and Tokuhisa, T. (2004). J. Immunol. 173, 883–891.
Castellino, F., and Germain, R.N. (2007). J. Immunol. 178, 778–787. Cui, W., and Kaech, S.M. (2010). Immunol. Rev. 236, 151–166. Cui, W., Liu, Y., Weinstein, J.S., Craft, J., and Kaech, S.M. (2011). Immunity 35, this issue, 792–805. Foulds, K.E., Rotte, M.J., and Seder, R.A. (2006). J. Immunol. 177, 2565–2574.
Rutishauser, R.L., Martins, G.A., Kalachikov, S., Chandele, A., Parish, I.A., Meffre, E., Jacob, J., Calame, K., and Kaech, S.M. (2009). Immunity 31, 296–308. Siegel, A.M., Heimall, J., Freeman, A.F., Hsu, A.P., Brittain, E., Brenchley, J.M., Douek, D.C., Fahle, G.H., Cohen, J.I., Holland, S.M., and Milner, J.D. (2011). Immunity 35, this issue, 806–818. Yi, J.S., Ingram, J.T., and Zajac, A.J. (2010). J. Immunol. 185, 4835–4845. Yoshimura, A., Naka, T., and Kubo, M. (2007). Nat. Rev. Immunol. 7, 454–465.
A Local Role for CD103+ Dendritic Cells in Atherosclerosis Sammy Bedoui1 and William R. Heath1,* 1Department of Microbiology & Immunology, The University of Melbourne, Parkville 3010, Victoria, Australia *Correspondence: [email protected] DOI 10.1016/j.immuni.2011.11.005
In this issue of Immunity, Choi et al. (2011) analyzed the cellular composition of aortic vessels in normal and atherosclerotic mice, revealing the presence of conventional CD103+ DCs with a potentially protective influence on atherosclerosis. Atherosclerosis with its typical complications of stroke and heart attack continues to be the primary cause of death in westernized societies. In this issue of Immunity, Steinman and colleagues explore the cellular composition of normal and atherosclerotic aortic tissue, confirming the presence of macrophages and dendritic cells (DCs) of monocyte origin but also revealing the presence of a CD103+ DC subset that is developmentally dependent on FMS-like tyrosine kinase 3 receptor ligand (Flt3L) and is of nonmonocyte origin (Figure 1). Association of this DC population with atherosclerotic tissues appears to be protective and correlates with a relative increase in regulatory T (Treg) cells. A simplified view of atherosclerosis envisages a sequential model (Libby et al., 2011), whereby hemodynamic forces impacting on distinct areas of the vasculature, such as the lesser curvature of the
aortic arch, result in qualitative changes to endothelial cells lining these vessels. Changes include upregulation of adhesion molecules through which circulating monocytes gain access to the intima, an area of connective tissue located immediately below the basement membrane of the endothelium (Figure 1). Endothelial dysfunction also affects vessel wall permeability, promoting uptake and retention of circulating lipids, such as cholesterol-containing low-density lipoproteins (LDLs). These fatty particles are engulfed by monocyte-derived macrophages that eventually become engorged to histologically appear as ‘‘foam cells’’ (Lusis, 2000). The crystalline nature of some of these deposits not only makes their elimination by macrophages difficult, but also evokes inflammasome activation and the secretion of proinflammatory cytokines. The consequence of this inflammatory response is swelling of the intimal space,
perpetuation of endothelial dysfunction, further recruitment of leukocytes, and exacerbation of hemodynamic stress due to bulging of the lesion into the vessel lumen. When the endothelial lining eventually ruptures, platelet activation and thrombus formation lead to the characteristic atherosclerotic lesions that can either occlude the vessel lumen locally or, upon dislodgement, block distant arteries. Atherosclerosis is not only a critical medical concern, but represents an interesting disease for immunologists to study basic mechanisms of localized inflammation. Although atherosclerosis is associated with intimal immigration of a variety of leukocytes, including monocytes, DCs, T cells, B cells, and mast cells, it is widely believed that monocytederived macrophages are the dominant phagocytic cell type involved in the pathogenesis of this disease. Building
Immunity 35, November 23, 2011 ª2011 Elsevier Inc. 665
Immunity
Previews
Figure 1. Diagram of Aortic Regions with a Schematic Cross-section of the Vessel Wall Showing Developing Atherosclerosis The intima is infiltrated by monocyte-derived macrophages (CD11clo CD11b+ F4/80+ MHClo), some of which develop into foam cells upon accumulation of modified low density lipoproteins. The intima also contains monocyte-derived dendritic cells (CD11chi MHChi CD11b+ F4/80+) and a population of Flt3-dependent dendritic cells (CD11chi MHChi CD11b CD103+) that are not of monocyte origin. This latter population appears to be atheroprotective, possibly through their ability to interact with Treg cells.
on earlier work (Choi et al., 2009; Weber et al., 2008), Steinman and colleagues observed that aortic tissues contained a substantial proportion of cells with a DC phenotype (CD11chi MHC IIhi) (Figure 1). To ensure that these cells were indeed DCs, they performed a series of experiments. Combining flow cytometry and
immunofluorescence, they observed that CD11chi MHC IIhi cells increased in mice treated with the DC growth factor Flt3L, whereas the number of CD11clo F4/80+ cells remained unchanged. The latter cells were then revealed to be macrophages, given that they displayed excellent phagocytic activities, although
666 Immunity 35, November 23, 2011 ª2011 Elsevier Inc.
their ability to stimulate naive CD4+ and CD8+ T cells was poor. Conversely, CD11chi MHC IIhi cells took up beads poorly, but were efficient stimulators of T cells. Together with the selective absence of CD11clo F4/80+ cells in mice lacking macrophage colony stimulating factor, these findings show that the mouse aortic tissues examined here contained populations of macrophages (CD11clo F4/80+) and DCs (CD11chi MHC IIhi). Thus, whereas previous studies had reported the presence of cells with DC-like characteristics in vessel tissues, the present study defines what constitutes a macrophage and a DC in vessel tissues by using developmental and functional distinctions. It had been assumed that DCs found in aortic tissues were only of the inflammatory type that differentiates in situ from monocytes (Weber et al., 2008). The author’s first clue that this might not necessarily be the case came from immunohistology showing that not all CD11chi MHC IIhi cells coexpressed CD11b. Flow cytometry subsequently revealed that the aortic tissues contained two distinct types of DCs: one characterized by expression of high amounts of CD11b and F4/80 (CD11b+ DC) and another expressing low amounts of CD11b, but staining positive for the integrin CD103 (CD103+ DCs). This observation aligns very well with the DC subset composition of other peripheral organs, such as the skin or lungs, in which a distinct CD11b+ DC subset can be separated from CD103+ DCs (Heath and Carbone, 2009). Consistent with their disparate developmental origins, Steinman and colleagues found that CD103+ DCs were selectively increased in the presence of Flt3L and absent from aortic tissues of Flt3 / mice. In contrast, CD11b+ DCs were implicated to arise from monocytes through a series of experiments involving CD11b-DTR mice, Csf1 / mice, and in vivo labeling studies with an antibody against DC-SIGN. Thus, a key finding from this work is that the aortic intima contains conventional DCs that differentiate from Flt3-dependent precursors, rather than monocytes, in addition to the previously described monocyte-derived DCs. Importantly, Choi et al. (2011) find that the presence of Flt3-dependent CD103+ DCs is inversely correlated with aortic
Immunity
Previews lesions size, suggesting an atheroprotective role for this DC subset. On the basis of a relative increase in regulatory T cells within lesions, reduced tissue expression of mRNA for proinflammatory cytokines, and previous reports of atheroprotective effects of Treg cells (Ait-Oufella et al., 2006), the authors suggest that the protective role of CD103+ DC relates to their ability to regulate local Treg cell homeostasis. Although such a conclusion is consistent with reports of Treg cell stimulation by CD103+ DCs in the intestine (Coombes et al., 2007), these latter DCs express CD11b (Edelson et al., 2010) and are probably distinct from those in the aortic tissue. An important control experiment for these findings in Flt3 / mice was that plasma lipid profiles were not different relative to control mice, as at least some of the DCs that are missing in these mice could act as sinks for oxidized LDLs through their selective expression of the translocase CD36. One of the intriguing aspects of this study relates to the distribution of the different DC subsets throughout different anatomical parts of the ‘‘normal’’ aorta. The aortic sinus, which describes a widening of the aortic diameter at its origin at the heart, had more CD103+ DCs relative to CD11b+ DCs when compared to other areas such as the thoracic aorta. In this respect, it is also interesting to note that the increase in Flt3-sensitive DCs (CD103+ DCs) was very prominent at the opening of an arterial branch. This uneven distribution pattern between the two DC subsets in aortic tissues correlates nicely with the typical distribution pattern of atherosclerotic lesions, which develop predominantly at sites subjected
to strong hemodynamic forces, such as the aortic sinus, the lesser curvature of the aorta or branch points of smaller vessels. Although lesion development is much more accentuated in mouse models of atherosclerosis, atherosclerotic lesions also develop in normal mice and healthy humans. Immediate precursors to atherosclerotic lesions (‘‘fatty streaks’’) can be found in the aorta of healthy humans as early as in the first decade of life (Libby et al., 2011). It is therefore possible that the ‘‘normal’’ B6 mice utilized to analyze the distribution pattern of the DCs already had atherosclerotic lesions in these predilection spots and that the relative dominance of CD103+ DCs over CD11b+ DCs in these areas was a consequence of developing disease. The demonstration of elevated numbers of Flt3-dependent CD103+ DCs in atherosclerotic lesions of Ldlr / mice fed a high-fat diet further supports this view. It will be important to examine the causal relationship between this increase and the development of atherosclerotic lesions. Because CD103+ DCs usually reside in the tissues and upon maturation migrate via afferent lymphatics into the local draining lymph node (Heath and Carbone, 2009), it will also be interesting to examine whether CD103+ DCs migrate from the intima to draining LN. Whereas this study by Steinman and colleagues implicates CD103+ DCs in an atheroprotective role, it did not specifically address how monocyte-derived DCs contributed to atherosclerosis development. However, a very recent study shows that a type of CD11b+ DC characterized by the production of CCL17 appears to promote atheroscle-
rosis development and to inhibit Treg cell responses (Weber et al., 2011), raising the possibility that local Treg cell responses during atherosclerosis are regulated through a balance between inhibitory effects by monocyte-derived DCs and activating signals exerted by CD103+ DCs. Clearly more work is required to delineate precisely how these distinct types of DC impact on atherosclerosis development. REFERENCES Ait-Oufella, H., Salomon, B.L., Potteaux, S., Robertson, A.K., Gourdy, P., Zoll, J., Merval, R., Esposito, B., Cohen, J.L., Fisson, S., et al. (2006). Nat. Med. 12, 178–180. Choi, J.H., Do, Y., Cheong, C., Koh, H., Boscardin, S.B., Oh, Y.S., Bozzacco, L., Trumpfheller, C., Park, C.G., and Steinman, R.M. (2009). J. Exp. Med. 206, 497–505. Choi, J.H., Cheong, C., Dandamudi, D.B., Park, C.G., Rodriguez, A., Mehandru, S., Velinzon, K., and Jung, I. (2011). Immunity 35, this issue, 819–831. Coombes, J.L., Siddiqui, K.R., Arancibia-Ca´rcamo, C.V., Hall, J., Sun, C.M., Belkaid, Y., and Powrie, F. (2007). J. Exp. Med. 204, 1757–1764. Edelson, B.T., Kc, W., Juang, R., Kohyama, M., Benoit, L.A., Klekotka, P.A., Moon, C., Albring, J.C., Ise, W., Michael, D.G., et al. (2010). J. Exp. Med. 207, 823–836. Heath, W.R., and Carbone, F.R. (2009). Nat. Immunol. 10, 1237–1244. Libby, P., Ridker, P.M., and Hansson, G.K. (2011). Nature 473, 317–325. Lusis, A.J. (2000). Nature 407, 233–241. Weber, C., Zernecke, A., and Libby, P. (2008). Nat. Rev. Immunol. 8, 802–815. Weber, C., Meiler, S., Do¨ring, Y., Koch, M., Drechsler, M., Megens, R.T., Rowinska, Z., Bidzhekov, K., Fecher, C., Ribechini, E., et al. (2011). J. Clin. Invest. 121, 2898–2910.
Immunity 35, November 23, 2011 ª2011 Elsevier Inc. 667