| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Inhibitory receptors play crucial roles for fine regulation and termination of immune responses by negatively regulating cellular functions. A number of inhibitory receptors have been identified on various types of cells. In particular, inhibitory receptors on natural killer cells have been well characterized. It has been postulated that recognition of MHC class I, or related molecules, on target cells by inhibitory NK receptors allows NK cells to prevent self killing but destroy inappropriate cells possessing decreased levels of MHC class I.
Ly49Q is an ITIM-bearing inhibitory receptor belonging to Ly49 family that is known as one of subfamilies of NK receptors. Even though Ly49Q is classified into Ly49 family because of highly structural similarities and of its chromosomal location, Ly49Q has unique features different from other Ly49 family members. Ly49Q is not expressed on NK and NKT cells, but predominantly expressed on macrophages and plasmacytodi dendritic cells. Ly49Q has an abi
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lity to associate with both SHP-1 and SHP-2 in a tyrosine phosphorylation-dependent manner.
In this study, we explored role of Ly49Q in adhesion and migration of neutrophils using mice introducing with wild type (WT) or the ITIM-less mutant (YF) cDNA in both in vitro and in vivo. In the absence of inflammatory stimuli, Ly49Q-WT but not Ly49Q-YF inhibited firm adhesion and spreading by preventing of focal adhesion formation, suggesting that Ly49Q prevents hazardous adhesion in steady-state condition. In inflammatory situation, expression of Ly49Q-YF, which is incompetent for the ITIM-dependent signal, caused reduced tissue infiltration of neutrophils at an early stage. This was due to defects in organization of cellular polarity in response to fMLP. Contrary, Ly49Q-WT gave rise to the augmentation of neutrophil infiltration by the enhanced expression of Ly49Q. Furthermore, Ly49Q-WT, but not Ly49Q-YF mice, spontaneously developed hemorrhage in peripheral lymphoid organs accompanied with the increase in neutrophils. These functions of Ly49Q appeared to be mediated by regulating intracellular localization of associated SHP-1 in the chemoattractant stimuli-and the ITIM-dependent manner by changing own intracellular localization. Thus, Ly49Q on neutrophils is a pivotal molecule to regulate not only homeostatic regulation in steady state but also urgent migration upon inflammation. Less
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