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.
Show 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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