受者“Unlicensed”Ly49+NK细胞亚群在特异性调节异基因移植排斥反应中的作用及机制

NK细胞抑制性受体与配体（MHC-I类分子）不合在异基因造血干细胞移植中的作用备受瞩目，但目前临床研究结论并不一致，甚至相反。NK细胞，依据其抑制性受体是否识别自身MHC-I类分子，可分为"Licensed"和"Unlicensed"两个亚群。利用小鼠MHC不合异基因造血干细胞移植模型，申请人曾证明受者"Licensed"Ly49+NK细胞是参与异基因移植排斥反应的主要效应细胞；最近我们发现，受者"Unlicensed"Ly49+NK细胞有促进异基因移植物植入的作用。本课题拟继续探讨受者"Unlicensed"Ly49+NK细胞在异基因移植排斥反应中的作用及机制，研究受者"Unlicensed"Ly49+NK细胞抑制性受体与"非己"移植物配体相合或错配对异基因移植物植入、GVHD/GVT的不同影响，从免疫反应机制上阐明受者NK细胞抑制性受体与配体的最佳收益组合，为优化移植方案提供新思路。

Conflicting results have been reported regarding the effects of donor (or recipient) natural killer (NK) cell allo-reactivity resulting from recipients (or allograft) lacking MHC class I (ligand mismatch) for NK cell inhibitory receptors, on the clinical outcomes of allogeneic hematopoietic stem cell transplantation (AHSCT). Based on the inhibitory receptors of NK cells recognizing self MHC-I molecules or not, NK cells can be divided into two sub-populations: "licensed" or "unlicensed" NK cell subsets. We have previously reported that recipient "licensed" Ly49+ NK cell subsets are responsible for allo-rejection in murine transplantation models (Blood. 2012,119:1590-8). Recently, we found the differential effects of recipient "licensed" and "unlicensed" Ly49+ NK cell subsets on engraftment of allograft. The current project intends to determine the role and immune mechanism of recipient "unlicensed" Ly49+ NK cell subsets for specific regulation in allograft rejection. .Using a fully MHC-mismatched murine AHSCT model, C57BL/6 (H2b) used as donors and B10.D2 (H2d) used as recipients, the effects of recipient "unlicensed" Ly49+ ligand-matched NK cell subsets (expressing Ly49C/I which binds to donor H2b) allografts on recipient NK cell allo-reactivity will be investigated by examining allogeneic donor engraftment, as well graft-versus-host disease (GVHD)/graft-versus-tumor (GVT) effect. Our hypothesis is that allo-rejection could be down-regulated, after recognition of donor MHC class I by inhibitory receptors of recipient derived "unlicensed" Ly49+ NK cell subsets. The data obtained from this aim may have significant implications in the exploitation of NK cells post-AHSCT. This represents a novel means of using recipient NK cell subsets to facilitate allogeneic donor engraftment and balance GVHD and GVT effects.