Mannie M D, Truman H, Morrison-Plummer J
Department of Microbiology and Immunology, East Carolina University School of Medicine, Greenville, North Carolina 27858-4354.
Cell Immunol. 1994 Apr 1;154(1):484-97. doi: 10.1006/cimm.1994.1093.
Cloned and uncloned lines of encephalitogenic rat T cells produce IL-2 when activated with myelin basic protein (MBP) in the presence of irradiated splenocytes (SPL). Although these T cells use IL-2 as a primary mediator of autocrine growth, regulatory mechanisms controlling production of IL-2 have yet to be fully defined. This study shows that T cells reactivated within approximately 7 days of a prior activation were refractory to the reinduction of MBP-stimulated IL-2 production. In contrast, T cells rested for > 7 days regained the ability to produce optimal levels of IL-2 during activation with MBP. Cultures containing both activated and resting T cells responded to MBP by producing levels of IL-2 that were similar to those obtained from control cultures of resting T cells. The lack of IL-2 production during this refractory phase was associated with lowered responsiveness to MBP in proliferative assays as evidenced by right-shifted dose-response curves. However, this refractory phase did not affect the magnitude of responses elicited by optimal concentrations of MBP. The dissociation of proliferation from IL-2 production suggested parallel pathways of autocrine growth. Indeed, anti-MBP-proliferative responses were mediated by two distinct mechanisms distinguished by differential susceptibility to the anti-CD4 mAb W3/25. The W3/25-sensitive proliferation was desensitized in chronically activated T cells as well as in T cells activated once in the presence of the anti-CD4 mAb W3/25. Conversely, MBP responsiveness of W3/25-insensitive proliferation was unchanged by both chronic activation and by a prior activation in the presence of W3/25. In cultures of T cells recently activated by MBP in the presence of W3/25, the use of nonirradiated SPL rather than irradiated SPL reversed W3/25-mediated tolerance but did not restore MBP-stimulated IL-2 production. In summary, this study reveals mechanisms whereby the engagement of TcR and CD4 negatively regulates subsequent responsiveness of IL-2 production pathways and thereby impairs restimulation of IL-2-dependent proliferation by MBP-specific T-helper cells.
在经辐照的脾细胞（SPL）存在的情况下，用髓鞘碱性蛋白（MBP）激活时，致脑炎大鼠T细胞的克隆系和未克隆系均可产生白细胞介素-2（IL-2）。尽管这些T细胞将IL-2用作自分泌生长的主要介质，但控制IL-2产生的调节机制尚未完全明确。本研究表明，在先前激活后约7天内重新激活的T细胞对MBP刺激的IL-2产生的再诱导具有抗性。相反，静息超过7天的T细胞在被MBP激活期间恢复了产生最佳水平IL-2的能力。含有激活的T细胞和静息T细胞的培养物对MBP的反应是产生与静息T细胞对照培养物相似水平的IL-2。在这个不应期缺乏IL-2产生与增殖试验中对MBP的反应性降低有关，剂量反应曲线右移证明了这一点。然而，这个不应期并不影响最佳浓度MBP引发的反应幅度。增殖与IL-2产生的分离表明存在自分泌生长的平行途径。实际上，抗MBP增殖反应由两种不同机制介导，这两种机制通过对抗CD4单克隆抗体W3/25的不同敏感性来区分。W3/25敏感的增殖在慢性激活的T细胞以及在抗CD4单克隆抗体W3/25存在下激活一次的T细胞中均脱敏。相反，W3/25不敏感增殖的MBP反应性在慢性激活以及在W3/25存在下的先前激活后均未改变。在最近在W3/25存在下被MBP激活的T细胞培养物中，使用未辐照的SPL而非辐照的SPL可逆转W3/25介导的耐受性，但不能恢复MBP刺激的IL-2产生。总之，本研究揭示了T细胞受体（TcR）和CD4的参与负向调节IL-2产生途径的后续反应性，从而损害MBP特异性辅助性T细胞对IL-2依赖性增殖的再刺激的机制。
