Marginal zone B cells control the response of follicular helper T cells to a high-cholesterol diet

Nus, Meritxell; Sage, Andrew P.; Lu, Yuning; Masters, Leanne; Lam, Brian Y.H.; Newland, Stephen A.; Weller, Sandra; Tsiantoulas, Dimitrios; Raffort, Juliette; Marcus, Damiënne; Finigan, Alison; Kitt, Lauren; Figg, Nichola; Schirmbeck, Reinhold; Kneilling, Manfred; Yeo, Giles S.H.; Binder, Christoph J.; Pompa, José Luis de la; Mallat, Ziad

doi:10.1038/nm.4315

Cited by 125 publications

(153 citation statements)

References 57 publications

Supporting

Mentioning

138

Contrasting

Unclassified

Order By: Relevance

“…Tfh cells mutually interact with B cells contributing for high‐affinity antibody production in plasma cells . Additionally, recent studies have demonstrated that specific regulatory B cells dampen Tfh differentiation through their elevated PDL1 expression in the B‐cell marginal zone, our data demonstrate this function, as the higher frequency of PDL1 high B cells was accompanied by a reduced differentiation of Tfh cells in the spleen. However, in the MLNs the low frequency of regulatory B cells (CD19 + CD40 + PDL1 high ) did not result in a higher Tfh cell differentiation, possibly due to the regulatory profile of the interacting‐DCs (CD11c + MHCII + PDL1 + ).…”

Section: Discussionsupporting

confidence: 70%

Obesity affects peripheral lymphoid organs immune response in murine asthma model

et al. 2019

View full text Add to dashboard Cite

Summary Asthma and obesity present rising incidence, and their concomitance is a reason for concern, as obese individuals are usually resistant to conventional asthma treatments and have more exacerbation episodes. Obesity affects several features in the lungs during asthma onset, shifting the T helper type 2 (Th2)/eosinophilic response towards a Th17/neutrophilic profile. Moreover, those individuals can present reduced atopy and delayed cytokine production. However, the impact of obesity on follicular helper T (Tfh) cells and B cells that could potentially result in antibody production disturbances are still unclear. Therefore, we aimed to assess the peripheral response to ovalbumin (OVA) in a concomitant model of obesity and asthma. Pulmonary allergy was induced, in both lean and obese female BALB/c mice, through OVA sensitizations and challenges. Mediastinal lymph nodes (MLNs) and spleen were processed for immunophenotyping. Lung was used for standard allergy analysis. Obese‐allergic mice produced less anti‐OVA IgE and more IgG2a than lean‐allergic mice. Dendritic cells (CD11c+ MHCIIhigh) expressed less CD86 and more PDL1 in obese‐allergic mice compared with lean‐allergic mice, in the MLNs. Meanwhile, B cells (CD19+ CD40+) were more frequent and the amount of PDL1/PD1+ cells was diminished by obesity, with the opposite effects in the spleen. Tfh cells (CD3+ CD4+ CXCR5+ PD1+) expressing FoxP3 were more frequent in obese mice, associated with the predominance of Th (CD3+ CD4+) cells expressing interleukin‐4/GATA3 in the MLNs and interleukin‐17A/RORγT in the spleen. Those modifications to the main components of the germinal centers could be resulting in the increased IgG2a production, which – associated with the Th17/neutrophilic profile – contributes to asthma worsening and represents an important target for future treatment strategies.

show abstract

Section: Discussionsupporting

confidence: 70%

Obesity affects peripheral lymphoid organs immune response in murine asthma model

et al. 2019

View full text Add to dashboard Cite

show abstract

“…We, therefore, performed detailed flow cytometry phenotyping of B cell subsets in bone marrow, spleen, and peritoneum, including peritoneal B1 cells and splenic marginal zone B cells that are known to regulate atherosclerosis. 13,33,41 There were no differences in bone marrow B cell fractions in Ldlr…”

Section: /Xbp1mentioning

confidence: 91%

“…[25][26][27] We and others have shown follicular B2 cell interactions with CD4 + T cells, antagonized by marginal zone B2 cells, promote pathogenic T cell responses in the atherosclerotic setting. [28][29][30][31][32][33] Few models have, therefore, addressed the specific role of antibodies in isolation without impacting on other B cell functions. Altogether, it is hard to predict the …”

Section: Meet the First Author See P 198mentioning

confidence: 99%

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

Sage

Nus

Chakraborty

et al. 2017

Circulation Research

Self Cite

View full text Add to dashboard Cite

Rationale: Diverse B cell responses and functions may be involved in atherosclerosis. Protective antibody responses, such as those against oxidized lipid epitopes, are thought to mainly derive from T cell-independent innate B cell subsets. In contrast, both pathogenic and protective roles have been associated with T cell-dependent antibodies, and their importance in both humans and mouse models is still unclear.Objective: To specifically target antibody production by plasma cells and determine the impact on atherosclerotic plaque development in mice with and without CD4+ T cells. Methods and Results:We combined a model of specific antibody deficiency, B cell-specific CD79a-Cre x XBP1 (X-box binding protein-1) floxed mice (XBP1-conditional knockout), with antibody-mediated depletion of CD4+ T cells. Ldlr knockout mice transplanted with XBP1-conditional knockout (or wild-type control littermate) bone marrow were fed western diet for 8 weeks with or without anti-CD4 depletion. All groups had similar levels of serum cholesterol. In Ldlr/ XBP1-conditional knockout mice, serum levels of IgG, IgE, and IgM were significantly attenuated, and local antibody deposition in atherosclerotic plaque was absent. Antibody deficiency significantly accelerated atherosclerosis at both the aortic root and aortic arch. T cell and monocyte responses were not modulated, but necrotic core size was greater, even when adjusting for plaque size, and collagen deposition significantly lower. Anti-CD4 depletion in Ldlr/wild-type mice led to a decrease of serum IgG1 and IgG2c but not IgG3, as well as decreased IgM, associated with increased atherosclerosis and necrotic cores, and a decrease in plaque collagen. The combination of antibody deficiency and anti-CD4 depletion has no additive effects on aortic root atherosclerosis. Conclusions:

show abstract

“…Consistent with this concept is the finding that deficiency of PD-1 or PD-L1 in high fat-diet-fed Ldlr -/- mice enhances lesion development and plaque inflammation compared with baseline lesion development in wild-type mice that occurs despite the presence of PD-L1 (Lichtman, 2012). Similarly, a recent study shows that hypercholesterolemia induces PD-L1 expression on marginal zone B cells, which inhibits pro-atherogenic T follicular helper cell responses (Nus et al, 2017). …”

Section: Energy Metabolism Affects Immune Cell Function In Atherosclementioning

confidence: 97%

Monocyte-Macrophages and T Cells in Atherosclerosis

2017

View full text Add to dashboard Cite

Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein B-lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving, leading to arterial damage and thrombosis-induced organ infarction. The innate immune response is regulated at various stages, from hematopoiesis through monocyte changes and macrophage activation. The adaptive immune response is regulated primarily by mechanisms that affect the balance of regulatory vs. effector T cells. Mechanisms related to cellular cholesterol, phenotypic plasticity, metabolism, and aging play key roles in regulating these responses. Herein we review select topics that shed light on these processes and suggest new treatment strategies.

show abstract

Marginal zone B cells control the response of follicular helper T cells to a high-cholesterol diet

Cited by 125 publications

References 57 publications

Obesity affects peripheral lymphoid organs immune response in murine asthma model

Obesity affects peripheral lymphoid organs immune response in murine asthma model

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

Monocyte-Macrophages and T Cells in Atherosclerosis

Contact Info

Product

Resources

About