NKG7 enhances CD8+ T cell synapse efficiency to limit inflammation

Lelliott, Emily, Ramsbottom, Kelly, Dowling, Mark, Shembrey, Carolyn, Noori, Tahereh, Kearney, Conor, Michie, Jessica, Parish, Ian, Jordan, Margaret, Baxter, Alan, Young, Niel, Brennan, Amelia, and Oliaro, Jane (2022) NKG7 enhances CD8+ T cell synapse efficiency to limit inflammation. Frontiers in Immunology, 13. 931630.

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Abstract

Cytotoxic lymphocytes are essential for anti-tumor immunity, and for effective responses to cancer immunotherapy. Natural killer cell granule protein 7 (NKG7) is expressed at high levels in cytotoxic lymphocytes infiltrating tumors from patients treated with immunotherapy, but until recently, the role of this protein in cytotoxic lymphocyte function was largely unknown. Unexpectedly, we found that highly CD8+ T cell-immunogenic murine colon carcinoma (MC38-OVA) tumors grew at an equal rate in Nkg7+/+ and Nkg7-/- littermate mice, suggesting NKG7 may not be necessary for effective CD8+ T cell anti-tumor activity. Mechanistically, we found that deletion of NKG7 reduces the ability of CD8+ T cells to degranulate and kill target cells in vitro. However, as a result of inefficient cytotoxic activity, NKG7 deficient T cells form a prolonged immune synapse with tumor cells, resulting in increased secretion of inflammatory cytokines, including tumor necrosis factor alpha (TNF). By deleting the TNF receptor, TNFR1, from MC38-OVA tumors, we demonstrate that this hyper-secretion of TNF compensates for reduced synapse-mediated cytotoxic activity against MC38-OVA tumors in vivo, via increased TNF-mediated tumor cell death. Taken together, our results demonstrate that NKG7 enhances CD8+ T cell immune synapse efficiency, which may serve as a mechanism to accelerate direct cytotoxicity and limit potentially harmful inflammatory responses.

Item ID: 74901
Item Type: Article (Research - C1)
ISSN: 1664-3224
Keywords: NKG7,cytotoxic T lymphocytes, immune synapse, tumor necrosis factor, immunotherapy, inflammation
Copyright Information: Copyright © 2022 Lelliott, Ramsbottom, Dowling, Shembrey, Noori, Kearney, Michie, Parish, Jordan, Baxter, Young, Brennan and Oliaro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Funders: National Health and Medical Research Council of Australia (NHMRC), National Breast Cancer Foundation, Peter MacCallum Cancer Foundation
Projects and Grants: NHMRC 1139626, Grant #IIRS-18-151
Date Deposited: 08 Jul 2022 03:30
FoR Codes: 31 BIOLOGICAL SCIENCES > 3105 Genetics > 310507 Genetic immunology @ 100%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200104 Prevention of human diseases and conditions @ 50%
28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 50%
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