Cytokine-deficient CD8+ Tc1 cells induced by IL-4: retained inflammation and perforin and Fas cytotoxicity but compromised long term killing of tumor cells.
Cytokine-deficient CD8+ Tc1 cells induced by IL-4: retained inflammation and perforin and Fas cytotoxicity but compromised long term killing of tumor cells.
复制标题
IL-4 诱导的细胞因子缺陷型 CD8 Tc1 细胞：保留炎症、穿孔素和 Fas 细胞毒性，但损害了肿瘤细胞的长期杀伤作用。
作者：
S. Sad;Li Li;T. Mosmann
在抗原刺激后，初始CD 8 + T细胞分化为分泌细胞因子IL-2、IFN-γ和TNF的细胞毒性Tc 1细胞，这有助于它们的增殖和效应子功能。我们以前已经表明，IL-4直接作用于分化的Tc 1细胞，损害随后的Con A诱导的IL-2的产生。由于IL-4在正常免疫应答期间可在Tc 1细胞附近产生，我们进一步分析了IL-4处理的Tc 1细胞的短期和长期功能。我们现在表明，这些细胞也有缺陷的IFN-γ，TNF和IL-10的合成，以响应抗原刺激。IL-2的合成是最敏感的，因为用更高数量的APC刺激IL-4处理的Tc 1细胞部分恢复IFN-γ、TNF和IL-10，但不恢复IL-2的合成。将同种异体特异性Tc 1细胞注射到表达靶抗原的小鼠中，发现IL-4处理的Tc 1细胞体内细胞因子合成减少。细胞因子合成的损失并没有损害短期效应器功能的Tc 1细胞，因为它们诱导过继转移受体小鼠的迟发型超敏反应，并保留穿孔素和Fas依赖的细胞溶解机制在体外。肿瘤靶细胞和肿瘤特异性Tc 1细胞的长期共培养表明，正常Tc 1细胞增殖并杀死肿瘤细胞，而IL-4处理的Tc 1细胞不能增殖，因此不能抑制肿瘤细胞的增殖。这些结果表明，IL-4在体内的合成不会影响分化的Tc 1细胞的直接效应功能，但会损害免疫力，降低其长期的功能能力。
After antigenic stimulation, naive CD8+ T cells differentiate into cytotoxic Tc1 cells secreting the cytokines IL-2, IFN-gamma, and TNF, which aid their proliferation and effector functions. We have previously shown that IL-4 acts directly on differentiated Tc1 cells to impair subsequent Con A-induced IL-2 production. As IL-4 may be produced in the vicinity of Tc1 cells during normal immune responses, we have further analyzed the short and long term functions of IL-4-treated Tc1 cells. We now show that these cells also have a defect in the synthesis of IFN-gamma, TNF, and IL-10 in response to antigenic stimulation. IL-2 synthesis was the most sensitive, as stimulation of IL-4-treated Tc1 cells with higher numbers of APCs partially restored IFN-gamma, TNF, and IL-10, but not IL-2, synthesis. Injection of allo-specific Tc1 cells into mice expressing the target Ag revealed reduced cytokine synthesis in vivo by IL-4-treated Tc1 cells. Loss of cytokine synthesis did not impair the short term effector functions of Tc1 cells, as they induced adoptively transferred delayed type hypersensitivity in recipient mice and retained both perforin- and Fas-dependent cytolytic mechanisms in vitro. Long term coculture of tumor targets and tumor-specific Tc1 cells indicated that normal Tc1 cells proliferated and killed tumor cells, whereas IL-4-treated Tc1 cells failed to proliferate and hence were unable to curtail the proliferation of tumor cells. These results suggest that IL-4 synthesis in vivo would not affect immediate effector functions of differentiated Tc1 cells, but would compromise immunity by reducing their long term functional capability.