title: Failure to upregulate cell surface PD-1 is associated with dysregulated stimulation of T cells by TGN1412-like CD28 superagonist.
abstract: 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.
authors.affiliation: a Medical Research Council Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology ; University of Liverpool ; Liverpool , UK.
authors.forename: Thilipan
authors.initials: T
authors.lastname: Thaventhiran
authors.forename: Naif
authors.initials: N
authors.lastname: Alhumeed
authors.forename: Han X A
authors.initials: HX
authors.lastname: Yeang
authors.forename: Swaminathan
authors.initials: S
authors.lastname: Sethu
authors.forename: Jocelyn S
authors.initials: JS
authors.lastname: Downey
authors.forename: Ahmad F
authors.initials: AF
authors.lastname: Alghanem
authors.forename: Adedamola
authors.initials: A
authors.lastname: Olayanju
authors.forename: Emma L
authors.initials: EL
authors.lastname: Smith
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cross
authors.forename: Steven D
authors.initials: SD
authors.lastname: Webb
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Williams
authors.forename: Adrian
authors.initials: A
authors.lastname: Bristow
authors.forename: Christina
authors.initials: C
authors.lastname: Ball
authors.forename: Richard
authors.initials: R
authors.lastname: Stebbings
authors.forename: Jean G
authors.initials: JG
authors.lastname: Sathish
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000494:pharmacology; D015153:Blotting, Western; D018106:CD28 Antigens / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology* / Q000378:metabolism; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C584933:CCR5 protein, human; D018106:CD28 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D019713:Receptors, CCR5; C509303:TGN-1412
keywords: APC, antigen presenting cell; CCR5, C-C chemokine receptor type 5; CD28 superagonist; CD28SA, CD28 superagonist; CK2, casein kinase 2; CTLA-4, cytotoxic T-Lymphocyte Antigen 4; IFNγ, interferon gamma; IL-2, interleukin 2; LAG-3, Lymphocyte-activation gene 3; LFA-1, lymphocyte function-associated antigen 1; MFI, mean fluorescence intensity; PBMC, peripheral blood mononuclear cells; PD-1; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; PTEN, phosphatase and tensin homolog; S-phase, synthesis phase; T cells; TCR, T cell receptor; TEMs, effector memory T cells; TGN1412; TIM-3, T cell immunoglobulin mucin 3; immunostimulatory biologics