Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci

Xu, Maria M.; Ménoret, Antoine; Nicholas, Sarah-Anne E; Guenther, S.; Sundberg, Eric J.; Zhou, Beiyan; Rodríguez, Annabelle; Murphy, Patrick A.; Vella, Anthony T.

doi:10.1152/ajpheart.00088.2019

Cited by 9 publications

(7 citation statements)

References 74 publications

(77 reference statements)

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“…Furthermore, CD8 T cells consistently associate with plaque development, so we chose to focus on them 20,21 . In the PCAL model, we observed a statistically significant 3-fold increase in CD8 T cells in the LCA under LDF, compared to the contralateral artery control, as we and others have reported previously 41,42 (Figure 4D&E). In ECKO mice, however, the expected increase of CD8 T cells in LDF vessels compared to contralateral normal laminar flow vessels did not occur (Figure 4D&E, P<0.01).…”

Section: Endothelium-specific Deletion Of Elavl1 Reduced Cd8 T Cells ...supporting

confidence: 87%

Endothelial Immunosuppression in Atherosclerosis : Translational Control by Elavl1/HuR

Nicholas,

Helming,

Ménoret

et al. 2024

Preprint

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Atherosclerotic plaques are defined by the accumulation of lipids and immune cells beneath the endothelium of the arterial intima. CD8 T cells are among the most abundant immune cell types in plaque, and conditions linked to their activation correlate with increased levels of cardiovascular disease. As lethal effectors of the immune response, CD8 T cell activation is suppressed at multiple levels. These checkpoints are critical in dampening autoimmune responses, and limiting damage in cardiovascular disease.Endothelial cells are well known for their role in recruiting CD8 T and other hematopoietic cells to low and disturbed flow (LDF) arterial regions that develop plaque, but whether they locally influence CD8 effector functions is unclear. Here, we show that endothelial cells can actively suppress CD8 T cell responses in settings of chronic plaque inflammation, but that this behavior is governed by expression of the RNA-binding protein Embryonic Lethal, Abnormal Vision-Like 1 (Elavl1). In response to immune cell recruitment in plaque, the endothelium dynamically shifts splicing of pre-mRNA and their translation to enhance expression of immune-regulatory proteins including C1q and CD27. This program is immuno-suppressive, and limited by Elavl1. We show this byCdh5(PAC)-CreERT2-mediated deletion of Elavl1 (ECKO), and analysis of changes in translation by Translating Ribosome Affinity Purification (TRAP). In ECKO mice, the translational shift in chronic inflammation is enhanced, leading to increased ribosomal association of C1q components and other critical regulators of immune response and resulting in a ∼70% reduction in plaque CD8 T cells. CITE-seq analysis of the remaining plaque T cells shows that they exhibit lower levels of markers associated with T cell receptor (TCR) signaling, survival, and activation. To understand whether the immunosuppressive mechanism occurred through failed CD8 recruitment or local modulation of T cell responses, we used a novelin vitroco-culture system to show that ECKO endothelial cells suppress CD8 T cell expansion—even in the presence of wild-type myeloid antigen-presenting cells, antigen-specific CD8 T cells, and antigen. Despite the induction of C1q mRNA by T cell co-culture in both wild-type and ECKO endothelial cells, we find C1q protein abundantly expressed only in co-culture with ECKO cells. Together, our data define a novel immune-suppressive transition in the endothelium, reminiscent of the transition of T cells to T-regs, and demonstrate the regulation of this process by Elavl1.

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Section: Endothelium-specific Deletion Of Elavl1 Reduced Cd8 T Cells ...supporting

confidence: 87%

Endothelial Immunosuppression in Atherosclerosis : Translational Control by Elavl1/HuR

Nicholas,

Helming,

Ménoret

et al. 2024

Preprint

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“…These data suggested that CD8 ϩ T cells have a dual role in the post-MI wound healing process. Similar to what was observed in Xu et al (27), this study demonstrates a strong role of CD8 ϩ T cell-mediated action on monocyte/ macrophage recruitment and activation.…”

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confidence: 90%

Adaptive immunity-driven inflammation and cardiovascular disease

Ilatovskaya

Halade

DeLeon‐Pennell

2019

American Journal of Physiology-Heart and Circulatory Physiology

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The adaptive immune response has recently emerged as an important factor in a wide variety of cardiovascular disorders including atherosclerosis, hypertension, cardiac remodeling, and heart failure; however, its role is not fully understood. Since an assortment of innate responsive cells, e.g., neutrophils and monocytes/macrophages, coordinate with adaptive immunity, e.g., T cells, dendritic cells, and B cells, the temporal response and descriptions pertinent to the cellular phenotype and inflammation processes, in general, need additional investigation, clarification, and consensus particularly in cardiovascular disease. This Perspectives article reviews the contributions of 15 articles (including 7 reviews) published in the American Journal of Physiology-Heart and Circulatory Physiology in response to the Call for Papers: Adaptive Immunity in Cardiovascular Disease. Here, we summarize the crucial reported findings at the cardiac, vascular, immune, and molecular levels and discuss the translational feasibility and benefits of future prospective research into the adaptive immune response. Readers are encouraged to evaluate the data and learn from this collection of novel studies.

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“…In human atherosclerotic plaques, the costimulatory receptor CD137 (4-1BB) was found to be expressed on activated T cells and to act in a TCR-independent manner [ 69 , 70 ]. This receptor belonging to the necrosis factor superfamily member serves as a costimulatory factor for T cells and drives T cell proliferation and cytokine production [ 69 , 71 ]. CD137 ligand (CD137L) is present on the cell surface of several APCs, including B cells, macrophages and dendritic cells, and increases in expression upon activation under chronic inflammatory conditions [ 70 ].…”

Section: Costimulation/-inhibition Of Cd8 + T Cmentioning

confidence: 99%

“…Treatment of Apoe −/− mice with a CD137 agonist caused increased T cell infiltration consisting mostly of CD8 + T cells, and elevated levels of proinflammatory cytokines [ 69 ]. Similarly, increased CD8 + T cell plaque infiltrates were seen in adoptive transfer experiments using wild type but not CD137-deficient CD8 + T cells specific for an unrelated antigen (ovalbumin) transferred into proprotein convertase subtilisin/kexin type 9 (PCSK9)-mediated hyperlipidemic mouse models upon ovalbumin immunization [ 71 ]. These lesional CD137 + effector CD8 + T cells promoted infiltration of endogenous CD8 + T cells with IFNγ-producing potential, whereas CD137-deficient CD8 + T cells exhibited impaired vessel infiltration, minimal IFN-γ production, and lead to also reduced infiltration of endogenous CD8 + T cells.…”

Section: Costimulation/-inhibition Of Cd8 + T Cmentioning

confidence: 99%

CD8+ T Cells in Atherosclerosis

Schäfer

Zernecke

2020

Cells

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Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8+ T cells. The CD8+ T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8+ T cells ameliorates atherosclerosis. CD8+ T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8+ T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8+ T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8+ T cells and their cytotoxic activity. CD8+ T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25+CD8+ T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8+ T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8+ T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8+ T cells in atherosclerosis.

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Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci

Cited by 9 publications

References 74 publications

Endothelial Immunosuppression in Atherosclerosis : Translational Control by Elavl1/HuR

Endothelial Immunosuppression in Atherosclerosis : Translational Control by Elavl1/HuR

Adaptive immunity-driven inflammation and cardiovascular disease

CD8+ T Cells in Atherosclerosis

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