Prell R A, Dearstyne E, Steppan L G, Vella A T, Kerkvliet N I
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA.
Toxicol Appl Pharmacol. 2000 Aug 1;166(3):214-21. doi: 10.1006/taap.2000.8971.
Studies have shown that blocking B7-mediated costimulation induces T cell tolerance via anergy or apoptosis. Provision of exogenous IL-2 can reverse or prevent the induction of tolerance. We have previously shown that TCDD-induced suppression of the CTL response to allogeneic P815 tumor cells is accompanied by decreased expression of CD86 (B7-2) as well as suppressed IL-2 and IFNgamma production. In the present studies, the role of IL-2 and IFNgamma and the analysis of inappropriate deletion of CD8(+) cells was examined. Administration of IL-2 on days 7-9 relative to the injection of P815 tumor cells dose-dependently increased the CTL activity and the generation of CD8(+) CTL effector cells in TCDD-treated mice. This increased CTL response was not due to recruitment of naive CTL precursors (CTLp), suggesting that a small pool of activated CTLp in TCDD-treated mice could respond to the IL-2. A much larger pool of activated CTLp in control mice was also expanded by IL-2 treatment. In contrast, treatment with IFNgamma during the same time period did not alter CTL activity in control or TCDD-treated mice. To address the possibility that insufficient IL-2 early in the response was responsible for the reduced pool of activated CTLp in TCDD-treated mice, IL-2 was administered on days 1-3 after P815 injection. However, not only did early treatment with IL-2 fail to restore the response in TCDD-treated mice, it suppressed the CTL response of non-TCDD-treated mice. To test whether exposure to TCDD induced apoptosis of activated CD8(+) T cells, phosphatidylserine (PS) expression was measured on various days after P815 tumor challenge. Surprisingly, the percentage of apoptotic CD8(+) T cells was significantly lower in TCDD-treated mice compared to controls throughout the allograft response. Similarly, exposure to TCDD failed to enhance peripheral deletion of Vbeta3(+)CD8(+) T cells after injection of the superantigen Staphylococcal enterotoxin A (SEA). Taken together, the data indicate that TCDD induces an early defect in CTLp activation that is not due to insufficient IL-2 or deletion of CD8(+) cells and may implicate a novel mechanism by which ligands of the Ah receptor disrupt CTL precursor activation.
研究表明，阻断B7介导的共刺激可通过无反应性或凋亡诱导T细胞耐受。提供外源性白细胞介素-2（IL-2）可逆转或预防耐受的诱导。我们之前已经表明，2,3,7,8-四氯二苯并对二恶英（TCDD）诱导的对同种异体P815肿瘤细胞的细胞毒性T淋巴细胞（CTL）反应抑制伴随着CD86（B7-2）表达的降低以及IL-2和γ干扰素（IFNγ）产生的抑制。在本研究中，检测了IL-2和IFNγ的作用以及对CD8(+)细胞不适当缺失的分析。相对于注射P815肿瘤细胞，在第7至9天给予IL-2剂量依赖性地增加了TCDD处理小鼠的CTL活性和CD8(+)CTL效应细胞的生成。这种增加的CTL反应不是由于幼稚CTL前体（CTLp）的募集，这表明TCDD处理小鼠中一小部分活化的CTLp可以对IL-2作出反应。对照小鼠中更大的活化CTLp池也通过IL-2处理而扩大。相比之下，在同一时期用IFNγ处理并没有改变对照或TCDD处理小鼠的CTL活性。为了解决TCDD处理小鼠中早期IL-2不足可能是活化CTLp池减少的原因这一可能性，在注射P815后第1至3天给予IL-2。然而，早期用IL-2处理不仅未能恢复TCDD处理小鼠的反应，反而抑制了未用TCDD处理小鼠的CTL反应。为了测试暴露于TCDD是否诱导活化的CD8(+)T细胞凋亡，在P815肿瘤攻击后的不同天数测量磷脂酰丝氨酸（PS）表达。令人惊讶的是，在整个同种异体移植反应中，TCDD处理小鼠中凋亡的CD8(+)T细胞百分比与对照相比显著更低。同样，暴露于TCDD未能增强注射超抗原葡萄球菌肠毒素A（SEA）后Vβ3(+)CD8(+)T细胞的外周缺失。综上所述，数据表明TCDD诱导CTLp活化的早期缺陷，这不是由于IL-2不足或CD8(+)细胞的缺失，可能涉及一种新机制，即芳烃受体的配体破坏CTL前体的活化。
