Failure to upregulate cell surface PD-1 is associated with dysregulated stimulation of T cells by TGN1412-like CD28 superagonist
| Autor: | Michael J. Cross, Emma Smith, Naif Alhumeed, Han Xian Aw Yeang, Adedamola Olayanju, Jean G. Sathish, Thilipan Thaventhiran, Dominic P. Williams, Jocelyn S. Downey, Richard Stebbings, Ahmad F. Alghanem, Steven D. Webb, Swaminathan Sethu, Adrian Bristow, Christina Ball |
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| Rok vydání: | 2014 |
| Předmět: |
CD4-Positive T-Lymphocytes
Receptors CCR5 T cell T-Lymphocytes Immunology Cell Blotting Western Programmed Cell Death 1 Receptor T cells Biology Antibodies Monoclonal Humanized 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation CD28 Antigens Cell Movement CD28 superagonist PD-1 medicine Cell Adhesion Immunology and Allergy Cytotoxic T cell Humans IL-2 receptor Cells Cultured 030304 developmental biology Cell Proliferation 0303 health sciences ZAP70 CD28 Endothelial Cells Membrane Proteins TGN1412 Flow Cytometry Lymphocyte Function-Associated Antigen-1 immunostimulatory biologics Cell biology Up-Regulation medicine.anatomical_structure Microscopy Fluorescence Immunologic Memory 030215 immunology Reports |
| Zdroj: | mAbs |
| ISSN: | 1942-0870 |
| Popis: | The CD28 superagonist (CD28SA) TGN1412 was administered to humans as an agent that can selectively activate and expand regulatory T cells but resulted in uncontrolled T cell activation accompanied by cytokine storm. The molecular mechanisms that underlie this uncontrolled T cell activation are unclear. Physiological activation of T cells leads to upregulation of not only activation molecules but also inhibitory receptors such as PD-1. We hypothesized that the uncontrolled activation of CD28SA-stimulated T cells is due to both the enhanced expression of activation molecules and the lack of or reduced inhibitory signals. In this study, we show that anti-CD3 antibody-stimulated human T cells undergo time-limited controlled DNA synthesis, proliferation and interleukin-2 secretion, accompanied by PD-1 expression. In contrast, CD28SA-activated T cells demonstrate uncontrolled activation parameters including enhanced expression of LFA-1 and CCR5 but fail to express PD-1 on the cell surface. We demonstrate the functional relevance of the lack of PD-1 mediated regulatory mechanism in CD28SA-stimulated T cells. Our findings provide a molecular explanation for the dysregulated activation of CD28SA-stimulated T cells and also highlight the potential for the use of differential expression of PD-1 as a biomarker of safety for T cell immunostimulatory biologics. |
| Databáze: | OpenAIRE |
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