SHP-1 localization to the activating immune synapse promotes NK cell tolerance in MHC class I deficiency.

Natural killer (NK) cells recognize virally infected cells and tumors. NK cell function depends on balanced signaling from activating receptors, recognizing products from tumors or viruses, and inhibitory receptors (such as KIR/Ly49), which recognize major histocompatibility complex class I (MHC-I) molecules. KIR/Ly49 signaling preserves tolerance to self but also conveys reactivity toward MHC-I-low target cells in a process known as NK cell education. Here, we found that NK cell tolerance and education were determined by the subcellular localization of the tyrosine phosphatase SHP-1. In mice lacking MHC-I molecules, uneducated, self-tolerant Ly49A <sup>+</sup> NK cells showed accumulation of SHP-1 in the activating immune synapse, where it colocalized with F-actin and the signaling adaptor protein SLP-76. Education of Ly49A <sup>+</sup> NK cells by the MHC-I molecule H2D <sup>d</sup> led to reduced synaptic accumulation of SHP-1, accompanied by augmented signaling from activating receptors. Education was also linked to reduced transcription of Ptpn6, which encodes SHP-1. Moreover, synaptic SHP-1 accumulation was reduced in NK cells carrying the H2D <sup>d</sup> -educated receptor Ly49G2 but not in those carrying the noneducating receptor Ly49I. Colocalization of Ly49A and SHP-1 outside of the synapse was more frequent in educated compared with uneducated NK cells, suggesting a role for Ly49A in preventing synaptic SHP-1 accumulation in NK cell education. Thus, distinct patterning of SHP-1 in the activating NK cell synapse may determine NK cell tolerance

Temporary threshold shift after impulse-noise during video game play: Laboratory data

OBJECTIVE: Prevention of temporary threshold shift (TTS) after laboratory-based exposure to pure-tones, broadband noise, and narrow band noise signals has been achieved, but prevention of TTS under these experimental conditions may not accurately reflect protection against hearing loss following impulse noise. This study used a controlled laboratory-based TTS paradigm that incorporated impulsive stimuli into the exposure protocol; development of this model could provide a novel platform for assessing proposed therapeutics. DESIGN: Participants played a video game that delivered gunfire-like sound through headphones as part of a target practice game. Effects were measured using audiometric threshold evaluations and distortion product otoacoustic emissions (DPOAEs). The sound level and number of impulses presented were sequentially increased throughout the study. STUDY SAMPLE: Participants were normal-hearing students at the University of Florida who provided written informed consent prior to participation. RESULTS: TTS was not reliably induced by any of the exposure conditions assessed here. However, there was significant individual variability, and a subset of subjects showed TTS under some exposure conditions. CONCLUSIONS: A subset of participants demonstrated reliable threshold shifts under some conditions. Additional experiments are needed to better understand and optimize stimulus parameters that influence TTS after simulated impulse noise