Programmed Cell Death-1 (PD-1) anchoring to the GPI-linked co-receptor CD48 reveals a novel mechanism to modulate PD-1-dependent inhibition of human T cells.

Autor: White D; Departments of Immunology and Respiratory Research, USA. Electronic address: della.white@boehringer-ingelheim.com., Cote-Martin A; Departments of Immunology and Respiratory Research, USA., Bleck M; Departments of Immunology and Respiratory Research, USA., Garaffa N; Cancer Immunology and Immune Modulation, USA., Shaaban A; Cancer Immunology and Immune Modulation, USA., Wu H; Biotherapeutics Discovery. Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06811 USA., Liu D; Biotherapeutics Discovery. Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06811 USA., Young D; Biotherapeutics Discovery. Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06811 USA., Scheer J; Biotherapeutics Discovery. Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06811 USA., Lorenz IC; Biotherapeutics Discovery. Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06811 USA., Nixon A; Biotherapeutics Discovery. Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06811 USA., Fine JS; Departments of Immunology and Respiratory Research, USA., Byrne FR; Departments of Immunology and Respiratory Research, USA., Mbow ML; Departments of Immunology and Respiratory Research, USA; Cancer Immunology and Immune Modulation, USA., Moreno-Garcia ME; Departments of Immunology and Respiratory Research, USA. Electronic address: morgarmig@gmail.com.
Jazyk: angličtina
Zdroj: Molecular immunology [Mol Immunol] 2023 Apr; Vol. 156, pp. 31-38. Date of Electronic Publication: 2023 Mar 06.
DOI: 10.1016/j.molimm.2023.02.007
Abstrakt: Activation of PD-1 by anchoring it to Antigen Receptor (AR) components or associated co-receptors represents an attractive approach to treat autoimmune conditions. In this study, we provide evidence that CD48, a common lipid raft and Src kinase-associated coreceptor, induces significant Src kinase-dependent activation of PD-1 upon crosslinking, while CD71, a receptor excluded from these compartments, does not. Functionally, using bead-conjugated antibodies we demonstrate that CD48-dependent activation of PD-1 inhibits proliferation of AR-induced primary human T cells, and similarly, PD-1 activation using PD-1/CD48 bispecific antibodies inhibits IL-2, enhances IL-10 secretion, and reduces NFAT activation in primary human and Jurkat T cells, respectively. As a whole, CD48-dependent activation of PD-1 represents a novel mechanism to fine tune T cell activation, and by functionally anchoring PD-1 with receptors other than AR, this study provides a conceptual framework for rational development of novel therapies that activate inhibitory checkpoint receptors for treatment of immune-mediated diseases.
Competing Interests: Declarations of interest None, all authors were employees of Boehringer-Ingelheim Pharmaceuticals Incorporated at the time of this work.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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