Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells

Schönle, Anne; Hartl, Frederike A.; Mentzel, Jan; Nöltner, Theresa; Rauch, Katharina S.; Prestipino, Alessandro; Wohlfeil, Sebastian A.; Apostolova, Petya; Hechinger, Anne Kathrin; Melchinger, Wolfgang; Fehrenbach, Kerstin; Guadamillas, Marta C.; Follo, Marie; Prinz, Gabriele; Ruess, Ann Katrin; Pfeifer, Dietmar; Pozo, Miguel Á. del; Schmitt‐Graeff, Annette; Duyster, Justus; Hippen, Keli; Blazar, Bruce R.; Schachtrup, Christian; Minguet, Susana; Zeiser, Robert

doi:10.1182/blood-2015-09-672428

Cited by 45 publications

(38 citation statements)

References 38 publications

(49 reference statements)

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“…Numerous early clinical trials with adenosine receptor agonists are ongoing or have been completed recently, including indications such as psoriasis, rheumatoid arthritis, sickle cell anemia, myocardial reperfusion, and nerve injury ( 84 ) and hold promise to become part of the therapeutic arsenal against inflammatory diseases. To interfere with a broad activation signal as it is exerted by nucleotides the inhibition of the central signal is most promising and modification of TCR signaling can lead to Treg development ( 85 ). Besides purinergic receptor inhibition promising targets are the γc receptor ( 86 ) or Janus kinases ( 87 , 88 ).…”

Section: Mechanisms To Counterbalance the Effects Of Nucleotidesmentioning

confidence: 99%

The Role of Purine Metabolites as DAMPs in Acute Graft-versus-Host Disease

Apostolova

Zeiser

2016

Front. Immunol.

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Acute graft-versus-host disease (GvHD) causes high mortality in patients undergoing allogeneic hematopoietic cell transplantation. An early event in the classical pathogenesis of acute GvHD is tissue damage caused by the conditioning treatment or infection that consecutively leads to translocation of bacterial products [pathogen-associated molecular patterns (PAMPs)] into blood or lymphoid tissue, as well as danger-associated molecular patterns (DAMPs), mostly intracellular components that act as pro-inflammatory agents, once they are released into the extracellular space. A subtype of DAMPs is nucleotides, such as adenosine triphosphate released from dying cells that can activate the innate and adaptive immune system by binding to purinergic receptors. Binding to certain purinergic receptors leads to a pro-inflammatory microenvironment and promotes allogeneic T cell priming. After priming, T cells migrate to the acute GvHD target organs, mainly skin, liver, and the gastrointestinal tract and induce cell damage that further amplifies the release of intracellular components. This review summarizes the role of different purinergic receptors in particular P2X7 and P2Y2 as well as nucleotides in the pathogenesis of GvHD.

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Section: Mechanisms To Counterbalance the Effects Of Nucleotidesmentioning

confidence: 99%

The Role of Purine Metabolites as DAMPs in Acute Graft-versus-Host Disease

Apostolova

Zeiser

2016

Front. Immunol.

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“…miR-199 has also been shown to regulate cell proliferation and survival, by targeting caveolin-2, a plasma membrane scaffolding protein involved in cellular growth control, and apoptosis (45). Interestingly, caveolin-1 has been shown to regulate TCR signal strength and Treg differentiation, whereby cav-1 − / − donor T-cells cause less severe GvHD and yield higher numbers of Tregs (46). Caveolin-1 and -2 share structural similarities and are commonly co-expressed (45), however, miR-199 regulation of caveolin-1 is less well established in non-cell line material.…”

Section: Discussionmentioning

confidence: 99%

Serum and Extracellular Vesicle Micrornas MiR-423, MiR-199 and MiR-93* As Biomarkers for Acute Graft Versus Host Disease

Crossland

Norden

Pearce

et al. 2016

Blood

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Acute graft-versus-host disease (aGvHD) is a major cause of adverse outcome in hematopoietic stem cell transplantation (HSCT), with a high incidence (20-50%). A novel, non-invasive diagnostic test to predict for prevalence and severity would enable improved prophylaxis and reduce morbidity. Circulatory microRNAs (miRNAs) miR-423, miR-199, miR-93*, and miR-377 have previously been associated with aGvHD in post-HSCT patient plasma, but validation is lacking and their expression within extracellular vesicles (EVs) has not been explored. This study replicated elevated serum expression of miR-423 (p < 0.001), miR-199 (p = 0.04), miR-93* (p < 0.001), and miR-377 (p = 0.03) in aGvHD, using a prognostic cohort of day 14 (D14) post-HSCT patient samples (n = 81). Expression also associated with disease severity. Further analysis at aGvHD diagnosis in an independent cohort (n = 65) confirmed high miR-423 (p = 0.02), miR-199 (p = 0.007), and miR-93* (p = 0.004) expression at disease onset. Investigation of expression patterns during early HSCT sequential timepoints (pre-HSCT to D28) identified elevated miRNAs at D7 post-HSCT in all transplant patients. In a novel investigation of miRNA expression in serum EVs (n = 15), miR-423 (p = 0.09), miR-199 (p = 0.008), and miR-93* (p = 0.001) levels were lower at D14 in patients who later developed aGvHD, and this was replicated for miR-423 (p = 0.02) and miR-199 (p = 0.04) (n = 47). Comparing serum to circulating EVs, at D14 patients remaining aGvHD-free had higher expression of miR-423 (p = 0.03), miR-199 (p = 0.009), and miR-93* (p = 0.002) in the EV fraction. Results verify the capacity for circulating miR-423, miR-199, and miR-93* as diagnostic and prognostic aGvHD biomarkers. The novel finding of their differential expression in EVs suggests a potential role in aGvHD etiology. KeY POinTs• Expression of miR-423, miR-199, and miR-93* in post-HSCT serum and extracellular vesicles is associated with aGvHD incidence and severity. • Differential expression in extracellular vesicles suggests these microRNAs may be implicated in the pathology of aGvHD.

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“…This defect was due to a deficient response via TCR/CD3, as LFA-1 affinity for ICAM-1 was unaffected upon TCR activation, in contrast to the lower clustering of the integrin (Borger et al, 2017 ), corresponding with the defective recruitment of LFA-1. In CD4 T cells, caveolin-1 plays a structural role and is needed for the optimal clustering of Lck and the TCR; T cell grafts from wild type and Cav1 −/− mice are equally potent at inducing graft vs. host disease (GVHD) when depleted of regulatory T cells (Tregs), indicating that Cav1 −/− Tregs are equally protective (Schonle et al, 2016 ). Caveolin-1 increases in DCs upon their maturation and facilitates their migration to the lymph node and the chemotaxis in response to CCL21.…”

Section: Reciprocal Reorganization At the T Cell And Antigen-presentimentioning

confidence: 99%

Adhesive Interactions Delineate the Topography of the Immune Synapse

Martín-Cófreces

Vicente‐Manzanares

Sánchez-Madrid

2018

Front. Cell Dev. Biol.

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T cells form adhesive contacts with antigen-presenting cells (APCs) as part of the normal surveillance process that occurs in lymph nodes and other tissues. Most of these adhesive interactions are formed by integrins that interact with ligands expressed on the surface of the APC. The interactive strength of integrins depends on their degree of membrane proximity as well as intracellular signals that dictate the conformation of the integrin. Integrins appear in different conformations that endow them with different affinities for their ligand(s). Integrin conformation and thus adhesive strength between the T cell and the APC is tuned by intracellular signals that are turned on by ligation of the T cell receptor (TCR) and chemokine receptors. During the different stages of the process, integrins, the TCR and chemokine receptors may be interconnected by the actin cytoskeleton underneath the plasma membrane, forming a chemical and physical network that facilitates the spatiotemporal dynamics, positioning, and function of these receptors and supports cell-cell adhesion during T cell activation, allowing it to perform its effector function.

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Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells

Abstract: Key Points Cav-1–deficient T cells preferentially differentiate into Tregs, which translates into lower GVHD severity in mice. Reduced TCR:Lck clustering in Cav-1–deficient T cells is responsible for reduced TCR downstream signaling events promoting Treg differentiation.

Cited by 45 publications

References 38 publications

The Role of Purine Metabolites as DAMPs in Acute Graft-versus-Host Disease

The Role of Purine Metabolites as DAMPs in Acute Graft-versus-Host Disease

Serum and Extracellular Vesicle Micrornas MiR-423, MiR-199 and MiR-93* As Biomarkers for Acute Graft Versus Host Disease

Adhesive Interactions Delineate the Topography of the Immune Synapse

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