Abe R, Peng T, Sailors J, Bucala R, Metz C N
Laboratories of. Vascular Biology and Medical Biochemistry, The Picower Institute for Medical Research, Manhasset, NY 11030, USA.
J Immunol. 2001 Jan 15;166(2):747-53. doi: 10.4049/jimmunol.166.2.747.
Macrophage migration inhibitory factor (MIF) has been shown to be a pivotal cytokine that mediates host inflammatory and immune responses. Recently, immunoneutralization of MIF has been found to inhibit tumor growth in mice; however, the contributing mechanisms underlying this effect have not been well defined. We investigated whether MIF plays a regulatory role in the expression of CTL activity. In a mouse model of the CTL response using the OVA-transfected tumor cell line EL4 (EG.7), we found that cultures of splenocytes obtained from EG.7-primed mice secrete high levels of MIF following Ag stimulation in vitro. Notably, parallel splenocyte cultures treated with neutralizing anti-MIF mAb showed a significant increase in the CTL response directed against EG.7 cells compared with control mAb-treated cultures. This effect was accompanied by elevated expression of IFN-gamma. Histological examination of the EG. 7 tumors from anti-MIF-treated animals showed a prominent increase in both CD4(+) and CD8(+) T cells as well as apoptotic tumor cells, consistent with the observed augmentation of CTL activity in vivo by anti-MIF. This increased CTL activity was associated with enhanced expression of the common gamma(c)-chain of the IL-2R that mediates CD8(+) T cell survival. Finally, CD8(+) T lymphocytes obtained from the spleens of anti-MIF-treated EG.7 tumor-bearing mice, when transferred into recipient tumor-bearing mice, showed increased accumulation in the tumor tissue. These data provide the first evidence of an important role for MIF in the regulation and trafficking of anti-tumor T lymphocytes in vivo.
巨噬细胞移动抑制因子（MIF）已被证明是介导宿主炎症和免疫反应的关键细胞因子。最近，发现对MIF进行免疫中和可抑制小鼠肿瘤生长；然而，这种效应背后的作用机制尚未完全明确。我们研究了MIF是否在CTL活性表达中发挥调节作用。在使用OVA转染的肿瘤细胞系EL4（EG.7）的CTL反应小鼠模型中，我们发现从用EG.7免疫的小鼠获得的脾细胞培养物在体外抗原刺激后分泌高水平的MIF。值得注意的是，与对照单克隆抗体处理的培养物相比，用中和抗MIF单克隆抗体处理的平行脾细胞培养物显示针对EG.7细胞的CTL反应显著增加。这种效应伴随着IFN-γ表达的升高。对抗MIF处理动物的EG.7肿瘤进行组织学检查发现，CD4(+)和CD8(+) T细胞以及凋亡肿瘤细胞均显著增加，这与抗MIF在体内观察到的CTL活性增强一致。这种增加的CTL活性与介导CD8(+) T细胞存活的IL-2R共同γ链的表达增强有关。最后，从抗MIF处理的荷EG.7肿瘤小鼠脾脏中获得的CD8(+) T淋巴细胞，当转移到受体荷瘤小鼠中时，在肿瘤组织中的积累增加。这些数据首次证明了MIF在体内抗肿瘤T淋巴细胞的调节和运输中起重要作用。
