Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction

Reiche, Myrthe E.; Toom, Myrthe den; Willemsen, Lisa; Os, Bram van; Gijbels, Marion J.J.; Gerdes, Norbert; Aarts, Suzanne A. B. M.; Lutgens, Esther

doi:10.1136/bmjdrc-2019-000829

Cited by 8 publications

(14 citation statements)

References 45 publications

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“…For the atherosclerosis studies, Cd40l fl/fl mice were successfully generated via insertion of loxP sites flanking exon 3, which enabled cre-mediated deletion of exon 3 causing a translational frameshift rendering downstream exons nonfunctional (Ozgene Pty Ltd, Bentley, Australia, Supplementary Fig. 1a ) 57 . Cd40 fl/fl mice were successfully generated via insertion of loxP sites flanking exons 2 and 3, which enabled cre-mediated deletion of exon 2 and 3 (Ozgene Pty Ltd, Bentley, Australia, Supplementary Fig.…”

Section: Methodsmentioning

confidence: 99%

Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease

et al. 2021

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Atherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. As CD40L exerts multiple functions depending on the cell-cell interactions involved, we sought to investigate the function of the most relevant CD40L-expressing cell types in atherosclerosis: T cells and platelets. Atherosclerosis-prone mice with a CD40L-deficiency in CD4+ T cells display impaired Th1 polarization, as reflected by reduced interferon-γ production, and smaller atherosclerotic plaques containing fewer T-cells, smaller necrotic cores, an increased number of smooth muscle cells and thicker fibrous caps. Mice with a corresponding CD40-deficiency in CD11c+ dendritic cells phenocopy these findings, suggesting that the T cell-dendritic cell CD40L-CD40 axis is crucial in atherogenesis. Accordingly, sCD40L/sCD40 and interferon-γ concentrations in carotid plaques and plasma are positively correlated in patients with cerebrovascular disease. Platelet-specific deficiency of CD40L does not affect atherogenesis but ameliorates atherothrombosis. Our results establish divergent and cell-specific roles of CD40L-CD40 in atherosclerosis, which has implications for therapeutic strategies targeting this pathway.

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Section: Methodsmentioning

confidence: 99%

Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease

et al. 2021

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“…33 We and others have shown that deletion of CD40 or CD40L on different-cell types differentially impact chronic inflammatory disease progression. 4,[11][12][13][14][15][16][17][18] Genetic studies in both patients and mice have shown that CD40L-CD40 signaling might affect BM haematopoiesis and, thus, inflammatory disease progression. 34 It was found that CD40L interaction with CD40 on HSCs induces CD40-TNF receptor associated factor (TRAF)6 signaling, which activated NFκB in HSCs.…”

Section: Discussionmentioning

confidence: 99%

“…13 Furthermore, T-cell specific CD40L-deficiency decreased atherosclerosis by affecting Th1 polarization and IFNγ production 10 , but did not affect weight gain or insulin resistance (IR) in mice with diet-induced obesity (DIO). 14 The CD40 -/mice showed reduced atherosclerosis 15 , as do macrophage 17 , and dendritic cell 10 specific CD40-deficient mice. However, full body CD40deficient mice displayed aggravated IR and severe AT inflammation during DIO 16,19 , whereas deficiency of macrophage CD40 only causes minor obesity related metabolic dysfunction.…”

Section: Introductionmentioning

confidence: 96%

“…Deletion of the co-stimulatory immune checkpoints CD40 or CD40L has shown different effects on haematopoiesis, obesity, the metabolic syndrome, and atherosclerosis. 4,[11][12][13][14][15][16][17][18][19] CD40L -/mice that were subjected to an obesogenic diet exhibited less weight gain, improved insulin resistance, and diminished AT inflammation. 13 Furthermore, T-cell specific CD40L-deficiency decreased atherosclerosis by affecting Th1 polarization and IFNγ production 10 , but did not affect weight gain or insulin resistance (IR) in mice with diet-induced obesity (DIO).…”

Section: Introductionmentioning

confidence: 99%

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Adipocytes control hematopoiesis and inflammation through CD40 signaling

et al. 2022

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The co-stimulatory CD40-CD40L dyad plays an important role in chronic inflammatory diseases associated with ageing. Although CD40 is mainly expressed by immune cells, CD40 is also present on adipocytes. We aimed to delineate the role of adipocyte-CD40 in the aging haematopoietic system and evaluated the effects of adipocyte CD40 deficiency on cardiometabolic diseases. Adult adipocyte CD40-deficient mice (AdiCD40KO) mice had a decrease in bone marrow (BM) haematopoietic stem cells (Lin-Sca+cKit+, LSK) and common lymphoid progenitors, which was associated with increased BM adiposity and T-cell activation, along with elevated plasma corticosterone levels, a phenotype that became more pronounced with age. Atherosclerotic AdiCD40koApoE-/- (CD40AKO) mice also displayed changes in the LSK population, showing increased myeloid- and lymphoid multipotent progenitors, and augmented corticosterone levels. Increased T-cell activation could be observed in BM, spleen, and adipose tissue (AT), while B-cell numbers were decreased. Although atherosclerosis was reduced in CD40AKO mice, plaques contained more activated T-cells and larger necrotic cores. Analysis of peripheral AT in a diet-induced obesity model revealed that obese AdiCD40KO mice showed increased T-cell activation in AT and lymphoid organs, but exhibited decreased weight gain and improved insulin sensitivity, along with increased fat oxidation. In conclusion, adipocyte CD40 plays an important role in maintaining immune cell homeostasis in BM during ageing and chronic inflammatory diseases, particularly of the lymphoid populations. Although adipocyte CD40-deficiency reduces atherosclerosis burden and ameliorates diet-induced obesity, the accompanying T-cell activation may eventually aggravate cardiometabolic diseases.

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“…[ 48 ] Therefore, the use of immune checkpoint inhibitors in T2D as a treatment strategy may have a double-edged sword effect whereby it improves T-cell mediated immune responses but further impairing glucose control, as reported elsewhere. [ 49 ] This emphasizes the need to find a fine balance between improving T-cell function while enhancing glucose metabolism when targeting PD-1 signaling as a therapeutic strategy in T2D patients. The overall impact of PD-1 signaling on T-cell function is illustrated in Fig.…”

Section: Discussionmentioning

confidence: 99%

A systematic review and meta-analysis on the regulation of programmed cell death-1 on T-cells in type 2 diabetes

et al. 2021

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Background: To assess T-cell exhaustion mediated by programmed cell death 1 (PD-1) pathway in patients living with type 2 diabetes (T2D). Methods: MEDLINE and ProQuest electronic databases were searched for eligible studies from inception up to February 2020. The risk of bias and the quality of evidence were independently assessed by two reviewers using the modified Newcastle-Ottawa Scale adapted for cross-sectional studies and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool, respectively. The random effects model was used to calculate effect estimates. Results: We identified 5 studies involving 380 participants which met the inclusion criteria. The pooled estimates showed elevated T helper cell exhaustion in patients with T2D in comparison to controls (mean difference [MD]: 2.57% [95% confidence interval [CI]: –3.84, 8.97]; I 2 = 100%, P < .00001). Likewise, T2D patients had increased levels of cytotoxic T-cells exhaustion (MD: 3.09% [95% CI: –12.96, 19.14]; I 2 = 100%, P < .00001). Although the upregulation of PD-1 on T-cells did not affect glucose metabolism-related profiles, it was associated with inflammation and the development of cardiovascular disease. Conclusion: In patients living with T2D, immune dysfunction is at least in part due to T-cell exhaustion mediated by the upregulation of PD-1 expression. Therefore, the use of immune checkpoint inhibitors as a therapeutic strategy may be beneficial in restoring immune function in patients with T2D.

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Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction

Cited by 8 publications

References 45 publications

Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease

Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease

Adipocytes control hematopoiesis and inflammation through CD40 signaling

A systematic review and meta-analysis on the regulation of programmed cell death-1 on T-cells in type 2 diabetes

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