ArticlePloS one2013
Targeting CD28, CTLA-4 and PD-L1 costimulation differentially controls immune synapses and function of human regulatory and conventional T-cells.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 69 citations in OpenAlex.
- CD80 as an Important Immune Mediator and Therapeutic Target in Atherosclerosis.International journal of molecular sciences · 2026Review
- RASA2 deletion rescues immune synapse dysfunction, enhancing CAR T cell efficacy against DMGs.Journal for immunotherapy of cancer · 2026Article
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- T Cell Resistance: On the Mechanisms of T Cell Non-activation.Immune network · 2024Review
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- A model of dysregulated crosstalk between dendritic, natural killer, and regulatory T cells in chronic obstructive pulmonary disease.Trends in immunology · 2024Article
- Tumor immunity: A brief overview of tumor‑infiltrating immune cells and research advances into tumor‑infiltrating lymphocytes in gynecological malignancies (Review).Experimental and therapeutic medicine · 2024Review
- Article
- Do Human iPSC-Derived Cardiomyocytes Cultured on PLA Scaffolds Induce Expression of CD28/CTLA-4 by T Lymphocytes?Journal of functional biomaterials · 2022Article
- A Rare Central Nervous System Involvement Due to CTLA-4 Gene Defect.Noro psikiyatri arsivi · 2022Article
- Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Inflammation and future depressive symptoms among recently bereaved spouses.Psychoneuroendocrinology · 2021Article
- Review
- Combined immune checkpoint blockade increases CD8+CD28+PD-1+ effector T cells and provides a therapeutic strategy for patients with neuroblastoma.Oncoimmunology · 2021Article
- SIRPγ-CD47 Interaction Positively Regulates the Activation of Human T Cells in Situation of Chronic Stimulation.Frontiers in immunology · 2021Article
- A Model for Apoptotic-Cell-Mediated Adaptive Immune EvasionFrontiers in pharmacology · 2019Article
- Molecular Mechanisms Involved in HCC Recurrence after Direct-Acting Antiviral Therapy.International journal of molecular sciences · 2018Review
- CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates.The Journal of clinical investigation · 2018Article
- CTLA‑4 interferes with the HBV‑specific T cell immune response (Review).International journal of molecular medicine · 2018Review
- T Cell Calcium Signaling Regulation by the Co-Receptor CD5.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
CD28, CTLA-4 and PD-L1, the three identified ligands for CD80/86, are pivotal positive and negative costimulatory molecules that, among other functions, control T cell motility and formation of immune synapse between T cells and antigen-presenting cells (APCs). What remains incompletely understood is how CD28 leads to the activation of effector T cells (Teff) but inhibition of suppression by regulatory T cells (Tregs), while CTLA-4 and PD-L1 inhibit Teff function but are crucial for the suppressive function of Tregs. Using alloreactive human T cells and blocking antibodies, we show here by live cell dynamic microscopy that CD28, CTLA-4, and PD-L1 differentially control velocity, motility and immune synapse formation in activated Teff versus Tregs. Selectively antagonizing CD28 costimulation increased Treg dwell time with APCs and induced calcium mobilization which translated in increased Treg suppressive activity, in contrast with the dampening effect on Teff responses. The increase in Treg suppressive activity after CD28 blockade was also confirmed with polyclonal Tregs. Whereas CTLA-4 played a critical role in Teff by reversing TCR-induced STOP signals, it failed to affect motility in Tregs but was essential for formation of the Treg immune synapse. Furthermore, we identified a novel role for PD-L1-CD80 interactions in suppressing motility specifically in Tregs. Thus, our findings reveal that the three identified ligands of CD80/86, CD28, CTLA-4 and PD-L1, differentially control immune synapse formation and function of the human Teff and Treg cells analyzed here. Individually targeting CD28, CTLA-4 and PD-L1 might therefore represent a valuable therapeutic strategy to treat immune disorders where effector and regulatory T cell functions need to be differentially targeted.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.