The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells

Sumit Sen Santara, Dian-Jang Lee, Ângela Crespo, Jun Jacob Hu, Caitlin Walker, Xiyu Ma, Ying Zhang, Sourav Chowdhury, Karla F. Meza-Sosa, Mercedes Lewandrowski, Haiwei Zhang, Marjorie Rowe, Arthur McClelland, Hao Wu, Caroline Junqueira () and Judy Lieberman ()
Additional contact information
Sumit Sen Santara: Boston Children’s Hospital
Dian-Jang Lee: Boston Children’s Hospital
Ângela Crespo: Boston Children’s Hospital
Jun Jacob Hu: Boston Children’s Hospital
Caitlin Walker: Boston Children’s Hospital
Xiyu Ma: Boston Children’s Hospital
Ying Zhang: Boston Children’s Hospital
Sourav Chowdhury: Harvard University
Karla F. Meza-Sosa: Boston Children’s Hospital
Mercedes Lewandrowski: Boston Children’s Hospital
Haiwei Zhang: Boston Children’s Hospital
Marjorie Rowe: Boston Children’s Hospital
Arthur McClelland: Harvard University
Hao Wu: Boston Children’s Hospital
Caroline Junqueira: Boston Children’s Hospital
Judy Lieberman: Boston Children’s Hospital

Nature, 2023, vol. 616, issue 7956, 348-356

Abstract: Abstract Natural killer (NK) cells kill infected, transformed and stressed cells when an activating NK cell receptor is triggered1. Most NK cells and some innate lymphoid cells express the activating receptor NKp46, encoded by NCR1, the most evolutionarily ancient NK cell receptor2,3. Blockage of NKp46 inhibits NK killing of many cancer targets4. Although a few infectious NKp46 ligands have been identified, the endogenous NKp46 cell surface ligand is unknown. Here we show that NKp46 recognizes externalized calreticulin (ecto-CRT), which translocates from the endoplasmic reticulum (ER) to the cell membrane during ER stress. ER stress and ecto-CRT are hallmarks of chemotherapy-induced immunogenic cell death5,6, flavivirus infection and senescence. NKp46 recognition of the P domain of ecto-CRT triggers NK cell signalling and NKp46 caps with ecto-CRT in NK immune synapses. NKp46-mediated killing is inhibited by knockout or knockdown of CALR, the gene encoding CRT, or CRT antibodies, and is enhanced by ectopic expression of glycosylphosphatidylinositol-anchored CRT. NCR1-deficient human (and Ncr1-deficient mouse) NK cells are impaired in the killing of ZIKV-infected, ER-stressed and senescent cells and ecto-CRT-expressing cancer cells. Importantly, NKp46 recognition of ecto-CRT controls mouse B16 melanoma and RAS-driven lung cancers and enhances tumour-infiltrating NK cell degranulation and cytokine secretion. Thus, NKp46 recognition of ecto-CRT as a danger-associated molecular pattern eliminates ER-stressed cells.

Date: 2023
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DOI: 10.1038/s41586-023-05912-0

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