NKG7 Enhances CD8+ T Cell Synapse Efficiency to Limit Inflammation

Frontiers in Immunology

Neil D. Young¹  Kelly M. Ramsbottom³  Tahereh Noori³  Jessica Michie³  Margaret A. Jordan⁴  Alan G. Baxter⁴  Amelia J. Brennan⁵  Jane Oliaro⁶  Carolyn Shembrey⁶  Emily J. Lelliott⁶  Ian A. Parish⁶  Mark R. Dowling⁶  Conor J. Kearney⁶ 

[1] Veterinary Sciences, James Cook University, Townsville, QLD, Australia;Central Clinical School, Monash University, Prahran, VIC, Australia;Centre for Cancer Immunotherapy, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;;College of Public Health, Medical &Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, Australia;Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Density and Health Sciences, The University of Melbourne, Parkville, VIC, Australia;

关键词: NKG7;    cytotoxic T lymphocytes;    immune synapse;    tumor necrosis factor;    immunotherapy;    inflammation;   

DOI  :  10.3389/fimmu.2022.931630

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown