Control of NK cell tolerance in MHC class I-deficiency by regulated SHP-1 localization to the activating immune synapse

Schmied, L.; Luu, T. T.; Sondergaard, J. N.; Meinke, S.; Mohammad, D. K.; Singh, S. B.; Mayer, C.; Perinetti Casoni, G.; Chrobok, M.; Schlums, H.; Rota, G.; Truong, H. M.; Westerberg, L. S.; Guarda, G.; Alici, E.; Wagner, A. K.; Kadri, N.; Bryceson, Y. T.; Saeed, M. B.; Hoglund, P.

doi:10.1101/2022.03.08.483415

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bioRxiv · 10.1101/2022.03.08.483415

Control of NK cell tolerance in MHC class I-deficiency by regulated SHP-1 localization to the activating immune synapse

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Abstract

Signaling via inhibitory KIR/Ly49 receptors preserves natural killer (NK) cell self-tolerance but also conveys NK cell reactivity towards MHC class-I low target cells in an education process. Here, we demonstrate that mouse NK cell education by H-2Dd regulates transcription of several genes in Ly49A+ NK cells including Ptpn6, encoding the phosphatase SHP-1. SHP-1 was highly expressed in uneducated NK cells, in which knock-out of Ptpn6 increased responsiveness. Following NKp46 triggering of uneducated NK cells, a higher synaptic abundance of phosphorylated SHP-1 was found relative to educated NK cells, concomitant with reduced phosphorylation of several signaling molecules, including PLC-g2, SLP-76, ZAP70/Syk and ERK1/2. SHP-1 overlapped extensively with F-actin and SLP-76 in the uneducated activating synapse of Ly49A+ NK cells, whereas a greater association between Ly49A and SHP-1 was observed in educated NK cells. Thus, our results indicate that in addition to transcriptional regulation, a distinct SHP-1 patterning in NK cell activating synapses can determine their tolerance.

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Schmied, L., Luu, T. T., Sondergaard, J. N., Meinke, S., Mohammad, D. K., Singh, S. B., Mayer, C., Perinetti Casoni, G., Chrobok, M., Schlums, H., Rota, G., Truong, H. M., Westerberg, L. S., Guarda, G., Alici, E., Wagner, A. K., Kadri, N., Bryceson, Y. T., Saeed, M. B., Hoglund, P.. 2022-03-09. Control of NK cell tolerance in MHC class I-deficiency by regulated SHP-1 localization to the activating immune synapse. https://doi.org/10.1101/2022.03.08.483415

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