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Siglec-7 represents a glyco-immune checkpoint for non-exhausted effector memory CD8+ T cells with high functional and metabolic capacities


Haas, Quentin; Markov, Nikita; Muerner, Lukas; Rubino, Viviana; Benjak, Andrej; Haubitz, Monika; Baerlocher, Gabriela M; Ng, Charlotte K Y; Münz, Christian; Riether, Carsten; Ochsenbein, Adrian F; Simon, Hans-Uwe; von Gunten, Stephan (2022). Siglec-7 represents a glyco-immune checkpoint for non-exhausted effector memory CD8+ T cells with high functional and metabolic capacities. Frontiers in Immunology, 13:996746.

Abstract

While inhibitory Siglec receptors are known to regulate myeloid cells, less is known about their expression and function in lymphocytes subsets. Here we identified Siglec-7 as a glyco-immune checkpoint expressed on non-exhausted effector memory CD8+ T cells that exhibit high functional and metabolic capacities. Seahorse analysis revealed higher basal respiration and glycolysis levels of Siglec-7+ CD8+ T cells in steady state, and particularly upon activation. Siglec-7 polarization into the T cell immune synapse was dependent on sialoglycan interactions in trans and prevented actin polarization and effective T cell responses. Siglec-7 ligands were found to be expressed on both leukemic stem cells and acute myeloid leukemia (AML) cells suggesting the occurrence of glyco-immune checkpoints for Siglec-7+ CD8+ T cells, which were found in patients' peripheral blood and bone marrow. Our findings project Siglec-7 as a glyco-immune checkpoint and therapeutic target for T cell-driven disorders and cancer.

Keywords: CD8+ T cells; Siglec-7; acute myeloid leukemia; hypersialylation; immune checkpoint; sialoglycans; tumor immunity and immunotherapy

Abstract

While inhibitory Siglec receptors are known to regulate myeloid cells, less is known about their expression and function in lymphocytes subsets. Here we identified Siglec-7 as a glyco-immune checkpoint expressed on non-exhausted effector memory CD8+ T cells that exhibit high functional and metabolic capacities. Seahorse analysis revealed higher basal respiration and glycolysis levels of Siglec-7+ CD8+ T cells in steady state, and particularly upon activation. Siglec-7 polarization into the T cell immune synapse was dependent on sialoglycan interactions in trans and prevented actin polarization and effective T cell responses. Siglec-7 ligands were found to be expressed on both leukemic stem cells and acute myeloid leukemia (AML) cells suggesting the occurrence of glyco-immune checkpoints for Siglec-7+ CD8+ T cells, which were found in patients' peripheral blood and bone marrow. Our findings project Siglec-7 as a glyco-immune checkpoint and therapeutic target for T cell-driven disorders and cancer.

Keywords: CD8+ T cells; Siglec-7; acute myeloid leukemia; hypersialylation; immune checkpoint; sialoglycans; tumor immunity and immunotherapy

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Life Sciences > Immunology
Uncontrolled Keywords:Immunology, Immunology and Allergy
Language:English
Date:23 September 2022
Deposited On:30 Jan 2023 11:01
Last Modified:30 Dec 2023 02:42
Publisher:Frontiers Research Foundation
ISSN:1664-3224
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.3389/fimmu.2022.996746
PubMed ID:36211376
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  • : FunderSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
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  • : FunderKrebsliga Schweiz
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  • : FunderHORIZON EUROPE Marie Sklodowska-Curie Actions
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  • : FunderKrebsliga Schweiz
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  • : FunderSchweizerische Multiple Sklerose Gesellschaft
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  • : FunderInnosuisse - Schweizerische Agentur für Innovationsförderung
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  • Content: Published Version
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)