B cell depletion skews cd4+ t cell towards a pro-inflammatory phenotype in aged atherosclerotic mice

B cell depletion skews cd4+ t cell towards a pro-inflammatory phenotype in aged atherosclerotic mice

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation ERA CVD Aims Aging is associated with changes in the composition and function of the immune system, such as decreased B cell numbers and reduced antibody responses (1). In addition,...

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Veröffentlicht in:Cardiovascular research 2022-06, Vol.118 (Supplement_1)
Hauptverfasser: De Mol, J, Postel, R, Smit, V, Bernabe Kleijn, MNA, Bot, I, Kuiper, J, Foks, AC
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container_issue Supplement_1
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container_title Cardiovascular research
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creator De Mol, J
Postel, R
Smit, V
Bernabe Kleijn, MNA
Bot, I
Kuiper, J
Foks, AC
description Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation ERA CVD Aims Aging is associated with changes in the composition and function of the immune system, such as decreased B cell numbers and reduced antibody responses (1). In addition, aging is related to an increased incidence of inflammatory diseases, such as the lipid-driven chronic inflammatory disease atherosclerosis, the main underlying cause of cardiovascular disease (2). B cells play a major role in atherosclerosis progression by antibody secretion, antigen presentation and T cell regulation. Different B cell subsets, with either proatherogenic or antiatherogenic properties, have been identified in atherosclerosis, but the impact of aging on B cells during atherosclerosis remains to be elucidated. In contrast to young atherosclerotic mice where few B cells are found within the plaque, single cell RNA sequencing and flow cytometry data from our group revealed that B cells are one of the most dominant leukocytes present in atherosclerotic aortas from naturally aged LDLr-/- mice. In this study, we aimed to gain further insights into the role of these aged B cells on T cell immunity in atherosclerosis by depleting B cells in aged atherosclerotic mice. Methods and Results Aged (85-95 weeks) atherosclerotic male LDLr-/- mice were kept on a chow diet for six weeks, during which the mice received 250 µg B cell-depleting anti-CD20 antibody (Genentech) (n=12) or 250 µg rat IgG2a isotype control (n=12) once a week intraperitoneally. Mice that received the anti-CD20 antibody showed effective B cell depletion in the blood and lymphoid organs, such as the spleen and lymph nodes, but also locally in the atherosclerotic plaque. In addition, B cell depleted mice showed a significant increase in the percentage of T-bet expressing CD4+ T cells in aortic plaques compared to control mice (αCD20: 25.05±2.88% vs. ctrl: 15.94±2.14%, p
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Main funding source(s): Dutch Heart Foundation ERA CVD Aims Aging is associated with changes in the composition and function of the immune system, such as decreased B cell numbers and reduced antibody responses (1). In addition, aging is related to an increased incidence of inflammatory diseases, such as the lipid-driven chronic inflammatory disease atherosclerosis, the main underlying cause of cardiovascular disease (2). B cells play a major role in atherosclerosis progression by antibody secretion, antigen presentation and T cell regulation. Different B cell subsets, with either proatherogenic or antiatherogenic properties, have been identified in atherosclerosis, but the impact of aging on B cells during atherosclerosis remains to be elucidated. In contrast to young atherosclerotic mice where few B cells are found within the plaque, single cell RNA sequencing and flow cytometry data from our group revealed that B cells are one of the most dominant leukocytes present in atherosclerotic aortas from naturally aged LDLr-/- mice. In this study, we aimed to gain further insights into the role of these aged B cells on T cell immunity in atherosclerosis by depleting B cells in aged atherosclerotic mice. Methods and Results Aged (85-95 weeks) atherosclerotic male LDLr-/- mice were kept on a chow diet for six weeks, during which the mice received 250 µg B cell-depleting anti-CD20 antibody (Genentech) (n=12) or 250 µg rat IgG2a isotype control (n=12) once a week intraperitoneally. Mice that received the anti-CD20 antibody showed effective B cell depletion in the blood and lymphoid organs, such as the spleen and lymph nodes, but also locally in the atherosclerotic plaque. In addition, B cell depleted mice showed a significant increase in the percentage of T-bet expressing CD4+ T cells in aortic plaques compared to control mice (αCD20: 25.05±2.88% vs. ctrl: 15.94±2.14%, p&lt;0.05). Furthermore, the percentage of RORyt+ and IL-17+ CD4+ T cells in the spleen and heart draining lymph nodes was increased after B cell depletion, indicating a shift towards Th17 differentiation. Conclusions Collectively, we show that CD20+ B cell depletion in aged LDLr-/- mice skews CD4+ T cells towards a Th1 phenotype in the atherosclerotic plaque and towards a Th17 phenotype in lymphoid organs, suggesting a protective role for aged B cells in atherosclerosis. However, B cells are a heterogeneous population and further research should elucidate whether aged B cells exert a pro- or anti-atherogenic role. In conclusion, our results indicate that aged B cells have an important function in CD4+ T cell differentiation and could be attractive targets to combat age-related cardiovascular disease.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvac066.230</identifier><language>eng</language><publisher>Oxford University Press</publisher><ispartof>Cardiovascular research, 2022-06, Vol.118 (Supplement_1)</ispartof><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2021. For permissions please email: Journals.permissions@oup.com. 2022</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>De Mol, J</creatorcontrib><creatorcontrib>Postel, R</creatorcontrib><creatorcontrib>Smit, V</creatorcontrib><creatorcontrib>Bernabe Kleijn, MNA</creatorcontrib><creatorcontrib>Bot, I</creatorcontrib><creatorcontrib>Kuiper, J</creatorcontrib><creatorcontrib>Foks, AC</creatorcontrib><title>B cell depletion skews cd4+ t cell towards a pro-inflammatory phenotype in aged atherosclerotic mice</title><title>Cardiovascular research</title><description>Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation ERA CVD Aims Aging is associated with changes in the composition and function of the immune system, such as decreased B cell numbers and reduced antibody responses (1). In addition, aging is related to an increased incidence of inflammatory diseases, such as the lipid-driven chronic inflammatory disease atherosclerosis, the main underlying cause of cardiovascular disease (2). B cells play a major role in atherosclerosis progression by antibody secretion, antigen presentation and T cell regulation. Different B cell subsets, with either proatherogenic or antiatherogenic properties, have been identified in atherosclerosis, but the impact of aging on B cells during atherosclerosis remains to be elucidated. In contrast to young atherosclerotic mice where few B cells are found within the plaque, single cell RNA sequencing and flow cytometry data from our group revealed that B cells are one of the most dominant leukocytes present in atherosclerotic aortas from naturally aged LDLr-/- mice. In this study, we aimed to gain further insights into the role of these aged B cells on T cell immunity in atherosclerosis by depleting B cells in aged atherosclerotic mice. Methods and Results Aged (85-95 weeks) atherosclerotic male LDLr-/- mice were kept on a chow diet for six weeks, during which the mice received 250 µg B cell-depleting anti-CD20 antibody (Genentech) (n=12) or 250 µg rat IgG2a isotype control (n=12) once a week intraperitoneally. Mice that received the anti-CD20 antibody showed effective B cell depletion in the blood and lymphoid organs, such as the spleen and lymph nodes, but also locally in the atherosclerotic plaque. In addition, B cell depleted mice showed a significant increase in the percentage of T-bet expressing CD4+ T cells in aortic plaques compared to control mice (αCD20: 25.05±2.88% vs. ctrl: 15.94±2.14%, p&lt;0.05). Furthermore, the percentage of RORyt+ and IL-17+ CD4+ T cells in the spleen and heart draining lymph nodes was increased after B cell depletion, indicating a shift towards Th17 differentiation. Conclusions Collectively, we show that CD20+ B cell depletion in aged LDLr-/- mice skews CD4+ T cells towards a Th1 phenotype in the atherosclerotic plaque and towards a Th17 phenotype in lymphoid organs, suggesting a protective role for aged B cells in atherosclerosis. However, B cells are a heterogeneous population and further research should elucidate whether aged B cells exert a pro- or anti-atherogenic role. In conclusion, our results indicate that aged B cells have an important function in CD4+ T cell differentiation and could be attractive targets to combat age-related cardiovascular disease.</description><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNqFkMtLAzEQxoMoWKtnrzkr22bz3qMWX1Dw0vsyzcOu7m6WJFr63xtp7x5mhuGb72P4IXRbk0VNGrY0P7EUGCLlgjJyhma1EqJilItzNCOE6EoyyS7RVUqfZRVC8Rmyj9i4vsfWTb3LXRhx-nL7hI3l9zgftRz2EG3CgKcYqm70PQwD5BAPeNq5MeTD5HA3YvhwFkPeuRiS6UvPncFDZ9w1uvDQJ3dzmnO0eX7arF6r9fvL2-phXRklSKVFA8xxClwII6jzjeZeaANgmd9SBVJITwXTW9YoKoWimmutuFRFZxbYHC2PsaY8kKLz7RS7AeKhrUn7x6gtjNoTo7YwKo67oyN8T_8e_wJoeWpT</recordid><startdate>20220610</startdate><enddate>20220610</enddate><creator>De Mol, J</creator><creator>Postel, R</creator><creator>Smit, V</creator><creator>Bernabe Kleijn, MNA</creator><creator>Bot, I</creator><creator>Kuiper, J</creator><creator>Foks, AC</creator><general>Oxford University Press</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20220610</creationdate><title>B cell depletion skews cd4+ t cell towards a pro-inflammatory phenotype in aged atherosclerotic mice</title><author>De Mol, J ; Postel, R ; Smit, V ; Bernabe Kleijn, MNA ; Bot, I ; Kuiper, J ; Foks, AC</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c750-859a3e42a455c52ef984f58caad3fb27a656f2538b3972657284887467d3f3da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>De Mol, J</creatorcontrib><creatorcontrib>Postel, R</creatorcontrib><creatorcontrib>Smit, V</creatorcontrib><creatorcontrib>Bernabe Kleijn, MNA</creatorcontrib><creatorcontrib>Bot, I</creatorcontrib><creatorcontrib>Kuiper, J</creatorcontrib><creatorcontrib>Foks, AC</creatorcontrib><collection>CrossRef</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>De Mol, J</au><au>Postel, R</au><au>Smit, V</au><au>Bernabe Kleijn, MNA</au><au>Bot, I</au><au>Kuiper, J</au><au>Foks, AC</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>B cell depletion skews cd4+ t cell towards a pro-inflammatory phenotype in aged atherosclerotic mice</atitle><jtitle>Cardiovascular research</jtitle><date>2022-06-10</date><risdate>2022</risdate><volume>118</volume><issue>Supplement_1</issue><issn>0008-6363</issn><eissn>1755-3245</eissn><abstract>Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation ERA CVD Aims Aging is associated with changes in the composition and function of the immune system, such as decreased B cell numbers and reduced antibody responses (1). In addition, aging is related to an increased incidence of inflammatory diseases, such as the lipid-driven chronic inflammatory disease atherosclerosis, the main underlying cause of cardiovascular disease (2). B cells play a major role in atherosclerosis progression by antibody secretion, antigen presentation and T cell regulation. Different B cell subsets, with either proatherogenic or antiatherogenic properties, have been identified in atherosclerosis, but the impact of aging on B cells during atherosclerosis remains to be elucidated. In contrast to young atherosclerotic mice where few B cells are found within the plaque, single cell RNA sequencing and flow cytometry data from our group revealed that B cells are one of the most dominant leukocytes present in atherosclerotic aortas from naturally aged LDLr-/- mice. In this study, we aimed to gain further insights into the role of these aged B cells on T cell immunity in atherosclerosis by depleting B cells in aged atherosclerotic mice. Methods and Results Aged (85-95 weeks) atherosclerotic male LDLr-/- mice were kept on a chow diet for six weeks, during which the mice received 250 µg B cell-depleting anti-CD20 antibody (Genentech) (n=12) or 250 µg rat IgG2a isotype control (n=12) once a week intraperitoneally. Mice that received the anti-CD20 antibody showed effective B cell depletion in the blood and lymphoid organs, such as the spleen and lymph nodes, but also locally in the atherosclerotic plaque. In addition, B cell depleted mice showed a significant increase in the percentage of T-bet expressing CD4+ T cells in aortic plaques compared to control mice (αCD20: 25.05±2.88% vs. ctrl: 15.94±2.14%, p&lt;0.05). Furthermore, the percentage of RORyt+ and IL-17+ CD4+ T cells in the spleen and heart draining lymph nodes was increased after B cell depletion, indicating a shift towards Th17 differentiation. Conclusions Collectively, we show that CD20+ B cell depletion in aged LDLr-/- mice skews CD4+ T cells towards a Th1 phenotype in the atherosclerotic plaque and towards a Th17 phenotype in lymphoid organs, suggesting a protective role for aged B cells in atherosclerosis. However, B cells are a heterogeneous population and further research should elucidate whether aged B cells exert a pro- or anti-atherogenic role. In conclusion, our results indicate that aged B cells have an important function in CD4+ T cell differentiation and could be attractive targets to combat age-related cardiovascular disease.</abstract><pub>Oxford University Press</pub><doi>10.1093/cvr/cvac066.230</doi></addata></record>
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title B cell depletion skews cd4+ t cell towards a pro-inflammatory phenotype in aged atherosclerotic mice
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