醫(yī)學免疫學課件：NK細胞記憶

1、NK細胞記憶OUTLINE背景知識固有免疫功能記憶功能小鼠實驗證據(jù)鼠巨細胞病毒誘導細胞因子誘導半抗原誘導人研究進展BACKGROUNDNK細胞無需抗原預先刺激不發(fā)生體細胞基因重排，依賴于一定數(shù)量的NKRs缺乏RAG重組酶依賴的克隆性抗原受體以及非特異的細胞毒作用BACKGROUD記憶性NK細胞二硝基氟苯 接觸性超敏反應模型無T、B淋巴細胞的小鼠仍可產(chǎn)生無T、B、NK細胞的小鼠不能產(chǎn)生EVIDENCE小鼠巨細胞病毒MCMV感染模型誘導抗原特異性的NK細胞記憶單純細胞因子誘導NK細胞記憶半抗原誘導的肝臟特有NK細胞記憶MCMV-INDUCED50%NK細胞表面表達Ly49H，特異性識別MCMV的M

2、157糖蛋白增值1000倍，持續(xù)存在并表現(xiàn)為活化表型凋亡至初始數(shù)量更多的IFN-更迅速MCMV-INDUCEDTimothyE. OSullivan, JosephC. Sun, LewisL. Lanier Natural Killer Cell Memorynull, Volume 43, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013MCMV-INDUCEDTimothyE. OSullivan, JosephC. Sun, LewisL. Lanier Natural Killer Cell Memorynull, Volume 4

3、3, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013MCMV-INDUCEDTimothyE. OSullivan, JosephC. Sun, LewisL. Lanier Natural Killer Cell Memorynull, Volume 43, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013嵌合小鼠NK細胞種類比例擴增與否缺乏M157的巨細胞病毒感染沒有擴增MCMV-INDUCEDTimothyE. OSullivan, JosephC. Sun, LewisL. Lan

4、ier Natural Killer Cell Memorynull, Volume 43, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013缺少DNAM-1、PKC和Fyn不能擴增MCMV-INDUCEDTimothyE. OSullivan, JosephC. Sun, LewisL. Lanier Natural Killer Cell Memorynull, Volume 43, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013IL-12受體激活STAT4激活轉錄因子Zbtb32拮抗

5、抑癌因子Blimp-1促進細胞增殖MCMV-INDUCED效應性NK細胞凋亡促活分子Bcl-2水平的降低促凋亡信號升高大多數(shù)細胞：破損的線粒體積累小部分細胞：誘導自噬，形成記憶性細胞MCMV-INDUCEDKLRG生成記憶細胞能力KLRG1：成熟NK細胞30%-50%，90-100%KLRG-1高，而SCA-1和CD27下調機體和病原體的相互作用非造血細胞上的Nod受體IL-15生成MCMV-INDUCED使用特定的細胞表面標志定義記憶性NK細胞：未完善！細胞表型與不同刺激有關CD69、CD43、KLRG1、Ly49H較高CD27較低記憶NK細胞比初始NK細胞更成熟CYTOKINE-INDUC

6、ED體外IL-12、IL-18預活化的NK細胞熒光蛋白標記7-22天之后仍可檢測體外二次刺激更強的免疫應答CYTOKINE-INDUCED無更強的細胞毒性對流感合胞病毒刺激產(chǎn)生免疫應答不具有抗原特異性輻射條件下，過繼傳輸過經(jīng)白細胞介素12/18和15預活化的NK細胞的小鼠具有更強的抗腫瘤能力HAPTEN-INDUCED半抗原致敏4-7天后重復刺激RAG缺陷型：可以產(chǎn)生免疫應答RAG和IL2受體鏈雙缺陷：不能產(chǎn)生免疫應答傳輸已被致敏的NK細胞：恢復肝臟HAPTEN-INDUCED肝臟？趨化因子受體CXCR6CXCL16：肝竇內皮細胞維持肝臟記憶性NK細胞的定居和生存，但與抗原識別無關HAPTEN

7、-INDUCEDHUMANNK細胞特異性缺陷將會導致機體無法控制病毒的感染HCMV、EB、單純皰疹病毒、水痘-帶狀皰疹病毒、人乳頭瘤病毒NKG2ChighCD57+NK細胞只發(fā)生在曾感染過巨細胞病毒的個體中HUMAN缺乏NKG2C的人體內抗巨細胞病毒IgG滴度增加：NK細胞功能異常免疫反應并未完全失效，可能NK細胞上還有其他受體代償機制HUMAN更廣泛的免疫應答流感疫苗非同源性流感病毒感染時，不能夠誘導足夠多的可交叉反應性的CD8 T細胞產(chǎn)生應答流感疫苗免疫后人NK細胞能夠短暫上調IFN-的表達SUMMARY現(xiàn)階段已有的研究成果人類疾病的防治癌癥的治療仍不明確的受體分子和作用通路人類領域應用角

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