过继单一pMHC特异性的同种CTL清除体内特定性状的靶细胞
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摘要
由于移植排斥反应的存在,T细胞对于同种细胞的应答通常被认为是有害的。然而伴随移植物抗宿主病(GVHD)发生的移植物抗白血病反应/移植物抗肿瘤反应,表明了同种反应性T细胞中存在一群有利的细胞,在清除恶性肿瘤中具有巨大作用。我们的前期工作提示同种T细胞与一般抗原反应性T细胞一样,识别的表位均为抗原肽/MHC复合物(pMHC),且均具有pMHC特异性,故在实际应用中有可能根据同种反应性T细胞的不同特异性将有利和不利的同种T细胞区分开。本研究拟在单个pMHC水平上,提供实验依据证实过继单一表位特异性的同种CTL可在体内清除特定性状的靶细胞,同时避免多组织损伤的发生。不仅有利于进一步认识同种反应发生的机制及其规律,而且为利用同种T细胞打破病理性耐受(慢性感染与肿瘤等)提供了新手段。
然而由于细胞表面存在极其繁多的pMHC,用传统的方法制备获得的同种反应性T细胞为针对多种表位的细胞群体。因此,本研究通过建立“单一表位特异性同种T细胞诱导体系”制备单一表位特异性同种CTL(胰岛素肽/H-2Kb特异性同种CTL),并过继输入动物体内,攻击表达该pMHC的靶细胞(H-2b小鼠的胰岛β细胞),观察其特异性杀伤效应。论文共分为三部分,其主要内容与结果如下：
一、制备H-2Kb/IgG2aFc分子,其能有效结合到C3H小鼠巨噬细胞表面
首先通过融合C57BL/6小鼠H-2Kb重链胞外段和IgG2aFc段获得H-2Kb/IgG2aFc融合基因,并与小鼠小鼠β2m基因分别插入杆状病毒双表达载体pFastBacTMDual的PP10和PPH启动子下游,利用昆虫杆状病毒表达系统表达以二聚体形式存在的β2m/H-2Kb/IgG2aFc分子(简称H-2Kb二聚体)。融合分子中IgG2aFc为高亲和力的Fc,可通过与FcR的相互作用加载H-2Kb二聚体到C3H小鼠巨噬细胞(H-2Kk)表面,使其能够“提呈”单一同种表位(特异性肽/H-2Kb),从而为诱导单一pMHC特异性的同种CTL奠定了基础。
二、体内外联合诱导自身/同系淋巴细胞产生胰岛素肽/H-2Kb特异性的同种CTL
利用加载了胰岛素肽/H-2Kb二聚体的自身巨噬细胞作为抗原刺激细胞,经过腹腔注射C3H小鼠(H-2Kk),诱导其产生针对胰岛素肽/H-2Kb表位的特异性同种T细胞,收集并对其进行特异性四聚体染色和细胞毒效应检测。结果显示诱导产生的CD8+T细胞特异性四聚体染色频率显著高于非特异性四聚体染色频率；同时,该CTL对具有相应表位(胰岛素肽/H-2Kb)的靶细胞具有明显的杀伤作用,而对无关表位的靶细胞杀伤率极低。
三、尾静脉过继诱生的单一pMHC特异性的同种T细胞定向损伤胰岛β细胞
将胰岛素肽/H-2Kb特异性CTL由尾静脉分别过继受者C57BL/6小鼠(H-2b)、B6C3F1小鼠(H-2b×k)和SCID beige小鼠(H-2d),过继后监测血糖、胰岛素及淋巴细胞浸润情况。结果显示接受过继后,受者C57BL/6和B6C3F1小鼠第3天便出现明显的血糖升高,胰岛素水平降低并且胰岛出现较明显的β细胞缺如和T细胞浸润；而受者SCID beige小鼠血糖和胰岛素水平未见明显变化,组织未见明显损伤。结果提示过继的单一pMHC特异性CTL能够定向杀伤特定性状的靶细胞。
本研究的创新点和意义：
1.提供直接的动物体内实验证据显示同种反应的发生机制,即任何抗原肽,只要能够与MHC分子结合,都能够形成同种T细胞的识别表位；同种反应性T细胞与一般抗原反应性T细胞一样,都具有pMHC特异性。
2.选用小鼠体内胰岛β细胞损伤作为观察同种CTL效应的指标,研究结果将显示过继特异性同种T细胞是干预病理性免疫耐受的新途径,同时为研究同种反应提供新的技术平台。
Although the T-cell response to allogeneic cells is typically regarded as a detrimental phenomenon responsible for rejection of transplanted allografts and graft-versus-host disease following haematopoietic stem cell transplantation, beneficial components also exist within the alloreactive population. The graft-versus-leukemia (GVLR) or graft-versus-tumor reaction (GVTR) accompanying with the graft-versus-host disease (GVHD) suggests the dramatic effect of the allogeneic T cells on eradicating malignant disease. And our previous studies suggest that it is the peptide/MHC complex as a whole recognized by allogeneic T cells and the recognition is pMHC specific. So it is possible to discriminate the good from the bad depending on their pMHC disparities. In this study, we aim to investigate alloreactivity at a single pMHC level and provide the in vivo experimental evidence that the transfused single pMHC specific allogeneic CTLs could target eliminating specified antigens without GVHD, which would pave the way for further exploring the mechanism and regulatory mode of allo-reactivity, in addition, add to our arsenal for breaking pathological immune tolerance.
However, because there are exceedingly wide range of cell surface pMHC complexes, it is essentially the combination of allogeneic T cells against multiple epitopes prepared with traditional access. Therefore, we set up a "single pMHC induction system " to prepare single pMHC specific CTLs (InsB/H-2Kb specific) and transfused the induced allogeneic CTLs to target imparing isletsβcells with InsB/H-2Kb expression.
1. Preparation of divalent H-2Kb/IgG2aFc and its binding to H-2Kk macrophages.
The H-2Kb/IgG2aFc hybrid gene was constructed by recombining cDNA coding for the extracellular domains (al,a2,a3) of H-2Kb with that for Fc fragment (Hinge,CH2,CH3) of murine IgG2a heavy chain. Then the hybrid H-2Kb/IgG2aFc sequence and mouseβ2m sequence were respectively inserted into the double promoters of pFastBacTMual vector for divalent H-2Kb/IgG2aFc expression (short for H-2Kb dimer).
The H-2Kb dimer consists of a divalent TCR-ligands and an IgG2aFc receptor (FcR) conjunctive moiety. And the H-2Kb dimer can be introduced as an allogeneic MHC molecule to Macrophages (H-2Kk) via the Fc and FcR interaction, which paves the way for generation of allogeneic CTLs with single pMHC specificity.
2. Preparing pMHC-specific, alloreactive CTLs through an in vivo primed plus ex vivo enhanced way.
Splenocytes of C3H (H-2Kk) were stimulated cells, while the H-2Kk macrophages (M(?)) bearing InsB/H-2Kb dimer were stimulating cells. The stimulating cells were i.p. injected into mouse C3H (H-2Kk) for InsB/H-2Kb specific, allogeneic CTLs induction. Splenocytes stimulated by autologous Mcp bearing the InsB/H-2Kb dimer were more frequently stained with the corresponding tetramer than those with irrelavent-tetramer and exhibited an elevated cytotoxicity against specific targets with InsB/H-2Kb epitope.
3. An insulin-producing P-cell targeted damage caused by i.v. adoptive transfusion of the induced allogeneic T cells
The InsB/H-2Kb-specific allogeneic T cells were i.v. transfused into recipient mice C57BL/6 (H-2b)、B6C3F1(H-2b×k) or SCID beige (H-2d). Then we monitored the variation in blood glucose concentration (BGC), serum insulin level and took out immuno-histochemical detection of pancreatic islets with anti-mouse CD3 or anti-mouse insulin antibody which turned out to be that on day 3 ater transfusion with InsB/H-2Kb-specific allogeneic T cells there was an increased BGC, decreased serum insulin, visible T cells infiltration and isletsβcells great loss in pancreatic islets of C57BL/6 and B6C3F1. While there was no corresponding changes in recipient SCID beige on the whole. Taken together, the target damage toβcells offered the in vivo evidence that the transfused allogeneic T cells could traffic to target sites and carry out the exact cytolytic effects in a pMHC-specific manner.
然而由于细胞表面存在极其繁多的pMHC,用传统的方法制备获得的同种反应性T细胞为针对多种表位的细胞群体。因此,本研究通过建立“单一表位特异性同种T细胞诱导体系”制备单一表位特异性同种CTL(胰岛素肽/H-2Kb特异性同种CTL),并过继输入动物体内,攻击表达该pMHC的靶细胞(H-2b小鼠的胰岛β细胞),观察其特异性杀伤效应。论文共分为三部分,其主要内容与结果如下：
一、制备H-2Kb/IgG2aFc分子,其能有效结合到C3H小鼠巨噬细胞表面
首先通过融合C57BL/6小鼠H-2Kb重链胞外段和IgG2aFc段获得H-2Kb/IgG2aFc融合基因,并与小鼠小鼠β2m基因分别插入杆状病毒双表达载体pFastBacTMDual的PP10和PPH启动子下游,利用昆虫杆状病毒表达系统表达以二聚体形式存在的β2m/H-2Kb/IgG2aFc分子(简称H-2Kb二聚体)。融合分子中IgG2aFc为高亲和力的Fc,可通过与FcR的相互作用加载H-2Kb二聚体到C3H小鼠巨噬细胞(H-2Kk)表面,使其能够“提呈”单一同种表位(特异性肽/H-2Kb),从而为诱导单一pMHC特异性的同种CTL奠定了基础。
二、体内外联合诱导自身/同系淋巴细胞产生胰岛素肽/H-2Kb特异性的同种CTL
利用加载了胰岛素肽/H-2Kb二聚体的自身巨噬细胞作为抗原刺激细胞,经过腹腔注射C3H小鼠(H-2Kk),诱导其产生针对胰岛素肽/H-2Kb表位的特异性同种T细胞,收集并对其进行特异性四聚体染色和细胞毒效应检测。结果显示诱导产生的CD8+T细胞特异性四聚体染色频率显著高于非特异性四聚体染色频率；同时,该CTL对具有相应表位(胰岛素肽/H-2Kb)的靶细胞具有明显的杀伤作用,而对无关表位的靶细胞杀伤率极低。
三、尾静脉过继诱生的单一pMHC特异性的同种T细胞定向损伤胰岛β细胞
将胰岛素肽/H-2Kb特异性CTL由尾静脉分别过继受者C57BL/6小鼠(H-2b)、B6C3F1小鼠(H-2b×k)和SCID beige小鼠(H-2d),过继后监测血糖、胰岛素及淋巴细胞浸润情况。结果显示接受过继后,受者C57BL/6和B6C3F1小鼠第3天便出现明显的血糖升高,胰岛素水平降低并且胰岛出现较明显的β细胞缺如和T细胞浸润；而受者SCID beige小鼠血糖和胰岛素水平未见明显变化,组织未见明显损伤。结果提示过继的单一pMHC特异性CTL能够定向杀伤特定性状的靶细胞。
本研究的创新点和意义：
1.提供直接的动物体内实验证据显示同种反应的发生机制,即任何抗原肽,只要能够与MHC分子结合,都能够形成同种T细胞的识别表位；同种反应性T细胞与一般抗原反应性T细胞一样,都具有pMHC特异性。
2.选用小鼠体内胰岛β细胞损伤作为观察同种CTL效应的指标,研究结果将显示过继特异性同种T细胞是干预病理性免疫耐受的新途径,同时为研究同种反应提供新的技术平台。
Although the T-cell response to allogeneic cells is typically regarded as a detrimental phenomenon responsible for rejection of transplanted allografts and graft-versus-host disease following haematopoietic stem cell transplantation, beneficial components also exist within the alloreactive population. The graft-versus-leukemia (GVLR) or graft-versus-tumor reaction (GVTR) accompanying with the graft-versus-host disease (GVHD) suggests the dramatic effect of the allogeneic T cells on eradicating malignant disease. And our previous studies suggest that it is the peptide/MHC complex as a whole recognized by allogeneic T cells and the recognition is pMHC specific. So it is possible to discriminate the good from the bad depending on their pMHC disparities. In this study, we aim to investigate alloreactivity at a single pMHC level and provide the in vivo experimental evidence that the transfused single pMHC specific allogeneic CTLs could target eliminating specified antigens without GVHD, which would pave the way for further exploring the mechanism and regulatory mode of allo-reactivity, in addition, add to our arsenal for breaking pathological immune tolerance.
However, because there are exceedingly wide range of cell surface pMHC complexes, it is essentially the combination of allogeneic T cells against multiple epitopes prepared with traditional access. Therefore, we set up a "single pMHC induction system " to prepare single pMHC specific CTLs (InsB/H-2Kb specific) and transfused the induced allogeneic CTLs to target imparing isletsβcells with InsB/H-2Kb expression.
1. Preparation of divalent H-2Kb/IgG2aFc and its binding to H-2Kk macrophages.
The H-2Kb/IgG2aFc hybrid gene was constructed by recombining cDNA coding for the extracellular domains (al,a2,a3) of H-2Kb with that for Fc fragment (Hinge,CH2,CH3) of murine IgG2a heavy chain. Then the hybrid H-2Kb/IgG2aFc sequence and mouseβ2m sequence were respectively inserted into the double promoters of pFastBacTMual vector for divalent H-2Kb/IgG2aFc expression (short for H-2Kb dimer).
The H-2Kb dimer consists of a divalent TCR-ligands and an IgG2aFc receptor (FcR) conjunctive moiety. And the H-2Kb dimer can be introduced as an allogeneic MHC molecule to Macrophages (H-2Kk) via the Fc and FcR interaction, which paves the way for generation of allogeneic CTLs with single pMHC specificity.
2. Preparing pMHC-specific, alloreactive CTLs through an in vivo primed plus ex vivo enhanced way.
Splenocytes of C3H (H-2Kk) were stimulated cells, while the H-2Kk macrophages (M(?)) bearing InsB/H-2Kb dimer were stimulating cells. The stimulating cells were i.p. injected into mouse C3H (H-2Kk) for InsB/H-2Kb specific, allogeneic CTLs induction. Splenocytes stimulated by autologous Mcp bearing the InsB/H-2Kb dimer were more frequently stained with the corresponding tetramer than those with irrelavent-tetramer and exhibited an elevated cytotoxicity against specific targets with InsB/H-2Kb epitope.
3. An insulin-producing P-cell targeted damage caused by i.v. adoptive transfusion of the induced allogeneic T cells
The InsB/H-2Kb-specific allogeneic T cells were i.v. transfused into recipient mice C57BL/6 (H-2b)、B6C3F1(H-2b×k) or SCID beige (H-2d). Then we monitored the variation in blood glucose concentration (BGC), serum insulin level and took out immuno-histochemical detection of pancreatic islets with anti-mouse CD3 or anti-mouse insulin antibody which turned out to be that on day 3 ater transfusion with InsB/H-2Kb-specific allogeneic T cells there was an increased BGC, decreased serum insulin, visible T cells infiltration and isletsβcells great loss in pancreatic islets of C57BL/6 and B6C3F1. While there was no corresponding changes in recipient SCID beige on the whole. Taken together, the target damage toβcells offered the in vivo evidence that the transfused allogeneic T cells could traffic to target sites and carry out the exact cytolytic effects in a pMHC-specific manner.
引文
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