Acidic pH inhibits non-MHC-restricted killer cell functions
Acidic pH inhibits non-MHC-restricted killer cell functions
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DOI：
10.1006/clim.2000.4904
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发表时间：
2000-09-01
影响因子：
8.6
通讯作者：
Kreutz, W
中科院分区：
文献类型：
--
作者：
Fischer, B;Müller, B;Kreutz, W
晚期实体瘤的免疫治疗策略通常收效甚微。已经讨论了允许肿瘤细胞从有效的抗肿瘤免疫应答中逃逸的各种机制。已知实体瘤会形成具有酸性间质pH的区域。在最近的一项在人体系统中进行的研究中，我们能够证明非MHC限制性细胞毒性受到酸性微环境的抑制。为了更深入地了解导致这种细胞毒性活性降低的机制，我们现在已经详细研究了酸性细胞外pH（pH（e））对杀伤过程的影响。未刺激的PBMC和LAK细胞用作效应细胞。这两种细胞群都能够通过穿孔素/颗粒酶或TNF α以MHC非依赖性方式杀伤肿瘤细胞，而只有IL-2激活的细胞可以通过Fas/FasL使用杀伤途径。我们研究了pH值下降对TNF α敏感和耐药以及Fas阳性和阴性靶细胞的不同杀伤途径的影响。在细胞外Ca 2+的情况下的实验用于区分Ca 2+依赖性穿孔素介导的杀伤。在这里，我们表明，释放穿孔素/颗粒酶的颗粒，分泌的TNF α，以及Fas/FasL相互作用或膜结合的TNF α的细胞毒性作用，大大抑制下降的pH值（e）。此外，激活细胞因子IFN γ的分泌以及下调细胞因子IL-10和TGF-β（1）的释放受到周围pH的严格影响。由于pH（e）为5.8导致细胞毒性效应细胞功能几乎完全丧失而不影响其活力，我们研究了pH（e）对基本细胞功能的影响，例如，我们发现随着pH（e）的下降，这两种功能的抑制作用增加。因此，酸性pH（e）明显损害基本的细胞调节，这最终阻止了计费过程。总之，我们的数据显示了各种杀伤细胞功能的严格pH（e）依赖性。因此，实体瘤内的酸性微环境可能有助于观察到的体内免疫抑制，从而分别损害抗肿瘤防御和免疫治疗。(C)北京大学出版社.
Immunotherapeutic strategies in advanced stages of solid tumors have generally met with Little success. Various mechanisms have been discussed permitting the escape of tumor cells from an effective antitumoral immune response. Solid tumors are known to develop regions with acidic interstitial pH. In a recent study performed in the human system, we were able to demonstrate that non-MHC-restricted cytotoxicity is inhibited by an, acidic microenvironment. To get more insight into the mechanisms leading to this reduced cytotoxic activity, we have now investigated the influence of an acidic extracellular pH (pH(e)) on the killing process in detail. Unstimulated PBMC and LAK cells were used as effector cells. Both populations are able to kill tumor cells in a MHC-independent manner via perforin/granzymes or TNF alpha, whereas only IL-2-activated cells can use the killing pathway via Fas/FasL. We studied the influence of a declining pH(e) on the different killing pathways against TNF alpha-sensitive and -resistant, as well, as Fas-positive and -negative, target cells. Experiments in the absence of extracellular Ca2+ were used to discriminate the Ca2+-dependent perforin-mediated killing. Here we show that the release of perforin/granzyme-containing granules, the secretion of TNF alpha, and also the cytotoxic action of Fas/FasL interaction or of membrane-bound TNF alpha were considerably inhibited by declining pH(e). Furthermore, the secretion of the activating cytokine IFN gamma, as well as the release of the down-regulating cytokines IL-10 and TGF-beta(1), was strictly influenced by surrounding pH. As a pH(e) of 5.8 resulted in a nearly complete loss of cytotoxic effector cell functions without affecting their viability, we investigated the influence of pH(e) on basic cellular functions, e.g., mitochondrial activity and regulation of intracellular pH. We found an increasing inhibition of both functions with declining pH(e). Therefore, an acidic pH(e) obviously impairs fundamental cellular regulation, which finally prevents the billing process. In summary, our data show a strict pH(e) dependence of various killer cell functions. Thus, an acidic microenvironment within solid tumors may contribute to the observed immunosuppression in vivo compromising antitumoral defense and immunotherapy in general, respectively. (C) 2000 Academic Press.