Lelliot, Emily J., Ramsbottom, Kelly M., Dowling, Mark R., Shewbrey, Carolyn, Noori, Tahereh, Kearney, Conor J., Michie, Jessica, Parish, Ian A., Jordan, Margaret A., Baxter, Alan G., Young, Niel D., Brennan, Amelia J., and Oliaro, Jane (2023) NKG7 Enhances CD8+ T cell synapse efficiency to limit inflammation. In: Baldari, Cosima T., Valitutti, Salvatore, and Dustin, Michael L, (eds.) Mechanisms of Lymphocyte Mediated Cytotoxicity in Health and Disease. Frontiers, Lausanne, Switzerland, pp. 156-170.

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Abstract

Cytotoxic lymphocytes are essential for anti-tumor immunity, and for effective responsesto 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:	79183
Item Type:	Book Chapter (Scholarly Work)
ISSN:	1664-8714
Copyright Information:	Each article within this ebook, and the ebook itself, are published under the most recent version of the Creative Commons CC-BY licence. The version current at the date of publication of this ebook is CC-BY 4.0. If the CC-BY licence is updated, the licence granted by Frontiers is automatically updated to the new version.
Date Deposited:	19 Jul 2023 05:22
FoR Codes:	32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320404 Cellular immunology @ 50% 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320409 Tumour immunology @ 50%
SEO Codes:	20 HEALTH > 2001 Clinical health > 200104 Prevention of human diseases and conditions @ 100%
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