T-cell co-stimulation by CD28–CD80/86 and its negative regulator CTLA-4 strongly influence accelerated atherosclerosis development

Ewing, M.M.; Karper, J.C.; Abdul, Shiraazkhan; Jong, Rob C. M. de; Peters, H.A.B.; Vries, Margreet R. de; Redeker, Anke; Kuiper, Johan; Toes, René E. M.; Arens, Ramon; Jukema, J. Wouter; Quax, Paul H.A.

doi:10.1016/j.ijcard.2012.12.085

Cited by 100 publications

(76 citation statements)

References 42 publications

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“…The immunoregulatory effect of a soluble fusion protein CTLA-4-Ig may involve blockade of CD80/CD86-CD28 pathway, which is one of the cell extrinsic mechanisms for CTLA-4-mediated immune regulation. Based on previous studies 15,16 and our data, we expect that CTLA-4 may be a possible therapeutic target for atherosclerotic disease. Given that CTLA-4-Ig has been already clinically used and has been shown to be effective for treating patients with rheumatoid arthritis who have high incidence of atherosclerotic cardiovascular disease, our findings imply that an immunomodulatory approach such as costimulatory blockade by CTLA-4-Ig may be effective for treating atherosclerosis and rheumatoid arthritis.…”

supporting

confidence: 51%

“…15 Moreover, another experimental study demonstrated that CTLA-4-Ig prevented intimal hyperplasia after vascular injury in hypercholesterolemic mice via reduction of Teff responses, and that CTLA-4 blockade using a blocking antibody significantly increased intimal thickening of the injured arteries. 16 Despite these previous studies, the role of CTLA-4 in atherosclerosis has not been fully elucidated.In the present study, we tested the hypothesis that overexpression of CTLA-4 would inhibit the development of atherosclerosis. To address this issue, we generated CTLA-4 transgenic apolipoprotein E-deficient (CTLA-4-Tg/Apoe −/− ) mice where T cells constitutively express CTLA-4 on the cell surface and intracellularly 17 on background prone to develop atherosclerosis.…”

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confidence: 99%

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Overexpression of Cytotoxic T-Lymphocyte–Associated Antigen-4 Prevents Atherosclerosis in Mice

Matsumoto

Sasaki

Yamashita

et al. 2016

ATVB

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Objective-Although T-cell-mediated chronic inflammation contributes to atherosclerosis development, the role of a negative regulatory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) in atherosclerosis is poorly understood. We investigated the effects of CTLA-4 overexpression on atherosclerosis in apolipoprotein E-deficient (Apoe −/− ) mice. Approach and Results-We generated CTLA-4 transgenic (CTLA-4-Tg)/Apoe −/− mice that display constitutive cell surface and intracellular expression of CTLA-4 in T cells and assessed atherosclerosis at age 16 weeks. CTLA-4 overexpression significantly reduced atherosclerotic lesion formation and intraplaque accumulation of macrophage and CD4 + T cells in the aortic root compared with controls. CTLA-4-Tg/Apoe −/− mice showed decreased numbers of effector CD4 + T cells and decreased expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, and a costimulatory molecule CD28, on CD11c + dendritic cells compared with controls. Consistent with in vivo findings, in vitro experiments revealed that CD4 + T cells from CTLA-4-Tg/Apoe −/− mice showed decreased proliferative capacity and proinflammatory cytokine production, downregulated CD80 expression on CD11c + dendritic cells, and suppressed the proliferation of other T cells by limiting the costimulatory pathway. Moreover, CD11c+ dendritic cells from CTLA-4-Tg/Apoe −/− mice showed reduced proliferative activity of T cells in vitro, suggesting the suppression of dendritic cell maturation in vivo. Correspondence to Naoto Sasaki, MD, PhD. Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. E-mail: sasakin@med.kobe-u.ac.jp 9 As a homolog of CD28, CTLA-4 binds to CD80/ CD86 and suppresses T-cell activation. CTLA-4-deficient mice die prematurely from multiorgan inflammation, indicating CTLA-4 as a potent negative regulator of T-cell immune responses. Overexpression of Cytotoxic T-Lymphocyte-Associated Antigen-4 Prevents Atherosclerosis in Mice10 Polymorphism of the CTLA-4 gene is reported to be associated with susceptibility to a variety of autoimmune diseases in humans.11 Moreover, germline heterozygous mutations in CTLA4 in humans have been shown to result in dysregulation of CD4 + Foxp3 + Tregs and hyperactivation of Teffs and B cells and cause complex immune dysregulation syndrome 12 although heterozygous Ctla4 deficiency in mice shows no autoimmune phenotype.10 CTLA-4 is important for Treg-mediated suppression of autoimmune diseases 13 and possibly atheroprotection although there is no direct evidence on its role in Treg-mediated atheroprotection. CTLA-4-Ig, a soluble fusion protein consisting of the extracellular CD80/CD86 binding portion of CTLA-4, has been shown to be beneficial for the treatment of autoimmune disease and prevention of organ rejection.14 CTLA-4-Ig might be beneficial for the prevention of atherosclerotic lesion formation in atherosclerotic mice under specific conditions, such...

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supporting

confidence: 51%

mentioning

confidence: 99%

Overexpression of Cytotoxic T-Lymphocyte–Associated Antigen-4 Prevents Atherosclerosis in Mice

Matsumoto

Sasaki

Yamashita

et al. 2016

ATVB

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“…Blockade of CTLA4 expression could promote T cell activation via the CD28/B7 signal pathway. 39 In our in vivo study, upregulation of the expression levels of MHC-II (signal 1) and CD80/CD86 (signal 2) by blockade of CTLA4 promoted T cell activation and proliferation.…”

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confidence: 66%

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

Zhao

et al. 2016

OncoImmunology

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Immature myeloid cells such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages play a vital role in the tumor immune escape and tumor progression. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4), as a negative immune checkpoint, is highly expressed in numerous solid tumors. However, precise functions of CTLA4 in head and neck squamous cell carcinoma (HNSCC) have not yet been elucidated. In this study, we demonstrated that the ratio of CD8 C /CTLA4 can be used as a potential index with a clinical prognostic value for HNSCC. Using immunocompetent transgenic mouse model with spontaneous HNSCC, we directly observed that targeting CTLA4 decreases MDSCs and M2 macrophages and promotes T cell activation in both tumor microenvironment and macro-environment. In all, our study provides direct evidence in vivo and proposes a rationale for CTLA4 inhibition as a future therapeutic strategy in patients with HNSCC.

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“…For example, blocking DC maturation through CD11c-specific knockdown of MyD88 altered the Treg-cell pool and accelerated atherosclerosis. 244 This is further supported by experiments showing that lack of inducible T-cell costimulator or programmed cell death 1, inhibitory pathways of the TNF superfamily, reduces Treg-cell capacity and lead to increased atherosclerosis, as does treatment with CTLA4-Ig (Abatacept), 245,246 which disrupts CD28-CD80/86 interactions. In terms of defining which subsets of cDCs are involved, Choi et al 227 demonstrate that the majority of Flt3 + pre-cDC-derived cells in normal and in atherosclerotic plaques are CD103 + DCs and that Flt3 deficiency increases atheorsclerosis, whereas CCL17 + DCs prevent the differentiation of naïve T cells into Treg cells through CCR4 and thus promote atherosclerosis.…”

Section: Functional Roles For Dcs In Atherosclerosismentioning

confidence: 93%

Adaptive (T and B Cells) Immunity and Control by Dendritic Cells in Atherosclerosis

Ait‐Oufella

Sage

Mallat

et al. 2014

Circulation Research

173

121

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14 Altogether, these early observations on the presence of T cells in human and in mouse atherosclerotic plaques remained associative and did not show causation.Subsequent studies using animal models of atherosclerosis, especially Apoe -/-or Ldlr -/-mice, in which human-like atherosclerotic lesions develop spontaneously or in response to high-fat diet, provided more direct evidence for the participation of adaptive immunity in atherogenesis. Apoe -/-or Ldlr -/-mice crossed with immunodeficient mice that lack the V(D)J recombination-activating protein 1 (Rag1) or have a severe combined immunodeficiency mutation (SCID; scid/scid mice) show, in general, reduced development of atherosclerotic lesions when fed a chow diet.5 These immunodeficient mice that lack both T and conventional B cells are not particularly informative on the role of specific T-and B-cell subpopulations that can be either pro-or antiatherogenic (see below). One study found no difference between immune-competent and immune-deficient mice fed a high-fat diet. 15The specific role of T cells was substantiated by experiments showing that the transfer of CD4 + T cells into scid/scid/ Apoe -/-mice fully reversed the atheroprotection provided by T/B deficiency. 16 However, when the effect of CD4 + T cells was evaluated in CD4-deficient Apoe -/-mice, contrasting results were reported. Female CD4 -/-Apoe -/-mice exhibited markedly larger lesions in the descending thoracic aorta, but no effect was observed in the aortic root when compared with wild-type (WT) Apoe -/-mice. 17 Intriguingly, in a subsequent study using the same CD4/Apoe double knockout mice, atherosclerosis in the aortic sinus was reduced, but the authors made no mention of the effect of CD4 + T-cell deficiency on atherosclerosis in the aorta.18 Of note, in both studies, the CD8 + cell population and the titers of anti-malondialdehyde (MDA)-oxidized lowdensity lipoprotein (oxLDL) IgM antibodies were increased. CD8 + T cells were recently shown to promote the development of vulnerable atherosclerotic plaques, 19 whereas natural antioxLDL IgM autoantibodies are atheroprotective 20 (see below). The specific recognition of peptide antigens presented by MHC molecules triggers TCR signaling, but costimulatory and coinhibitory receptors on T cells direct T-cell function and determine T-cell fate. These cosignaling molecules are members of the immunoglobulin superfamily, including B7 (CD80/86), CD28, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4 (CTLA4), and the tumor necrosis factor (TNF) receptor superfamily, including CD40, CD27, OX40, and CD137. Experiments aimed at investigating the role of cosignaling molecules provided further evidence for a role of T cells in atherogenesis 21,22 (see Functional roles for DCs in atherosclerosis section of this article). For example, blockade of the OX40-OX40L interaction by anti-OX40L antibody treatment in Ldlr -/-23 or Apoe -/-24 mice reduced atherosclerosis. Yet, blockade of T-cell activation was accompanied by an enhanced B-1 cell activity an...

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T-cell co-stimulation by CD28–CD80/86 and its negative regulator CTLA-4 strongly influence accelerated atherosclerosis development

Cited by 100 publications

References 42 publications

Overexpression of Cytotoxic T-Lymphocyte–Associated Antigen-4 Prevents Atherosclerosis in Mice

Overexpression of Cytotoxic T-Lymphocyte–Associated Antigen-4 Prevents Atherosclerosis in Mice

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

Adaptive (T and B Cells) Immunity and Control by Dendritic Cells in Atherosclerosis

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