Hernández-Caselles T, Stutman O
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
J Immunol. 1993 Oct 15;151(8):3999-4012.
Murine rTNF produces at least three effects on mouse thymocytes in vitro: 1) Is a modest co-stimulator of proliferation with low PHA-P doses. 2) Has a bi-directional interaction with rIL-6-depending on PHA concentration: at low PHA (5 to 10 micrograms/ml) TNF augments and at high PHA (20 to 30 micrograms/ml) inhibits IL-6-induced proliferation. A comparable bidirectional PHA dose-dependent TNF interaction was seen with IL-1 beta, whereas only inhibition at high PHA with IL-2 and only augmentation at low PHA with IL-4 were seen. 3) TNF induces direct thymocyte apoptosis (a property not shared by IL-1 beta, IL-2, IL-4, IL-6 and IL-7). Of the cytokines studied, only IL-7 reduced TNF apoptosis. Thymocyte apoptosis by TNF showed the same species specificity as costimulation (i.e., human TNF had no effect) and was not inhibited by CY. The thymocyte CD4-CD8 phenotype after 72-h cultures showed that TNF decreased mainly double negative (DN) and single positive (SP) subsets, whereas IL-6 with low or high PHA increased DN and SP, especially the SP CD8+ subset. The regulatory and apoptotic effects of TNF were seen only with thymocytes and not with peripheral splenic or lymph node T cells. Four mAb to mouse TNF (2E2, XT22, 1C6, and 1OD9) could abrogate TNF costimulation and the TNF effects on IL-6-induced thymocyte proliferation, at both augmenting and inhibitory PHA conditions. However, only the two antibodies that also neutralize TNF lytic activity (2E2, XT22) could inhibit TNF-mediated apoptosis, implying two different but neighboring functional domains in the TNF molecule mediating apoptosis/lysis and costimulation. Our studies show that TNF might have unique and complex regulatory effects on growth and death of thymocyte populations in adult mice quite different from its effects on T cells in periphery.
小鼠重组肿瘤坏死因子（rTNF）在体外对小鼠胸腺细胞至少产生三种效应：1）在低剂量植物血凝素-P（PHA-P）时，是一种适度的增殖共刺激因子。2）与重组白细胞介素-6（rIL-6）存在双向相互作用，这取决于PHA浓度：在低PHA（5至10微克/毫升）时，TNF增强rIL-6诱导的增殖，而在高PHA（20至30微克/毫升）时，TNF抑制rIL-6诱导的增殖。在与白细胞介素-1β（IL-1β）相互作用时，也观察到类似的双向PHA剂量依赖性TNF相互作用，而在高PHA时，TNF仅抑制IL-2诱导的增殖，在低PHA时，TNF仅增强IL-4诱导的增殖。3）TNF诱导胸腺细胞直接凋亡（这一特性不为IL-1β、IL-2、IL-4、IL-6和IL-7所共有）。在所研究的细胞因子中，只有IL-7能减少TNF诱导的凋亡。TNF诱导的胸腺细胞凋亡与共刺激表现出相同的物种特异性（即人TNF无作用），且不受环磷酰胺（CY）抑制。72小时培养后的胸腺细胞CD4-CD8表型显示，TNF主要减少双阴性（DN）和单阳性（SP）亚群，而低PHA或高PHA条件下的IL-6则增加DN和SP亚群，尤其是SP CD8+亚群。TNF的调节和凋亡作用仅在胸腺细胞中可见，在外周脾或淋巴结T细胞中则未观察到。四种抗小鼠TNF的单克隆抗体（2E2、XT22、1C6和1OD9）在增强和抑制PHA条件下，均可消除TNF共刺激以及TNF对IL-6诱导胸腺细胞增殖的影响。然而，只有两种也能中和TNF溶解活性的抗体（2E2、XT22）能够抑制TNF介导的凋亡，这意味着TNF分子中存在两个不同但相邻的功能域，分别介导凋亡/溶解和共刺激。我们的研究表明，TNF可能对成年小鼠胸腺细胞群体的生长和死亡具有独特而复杂的调节作用，这与其对外周T细胞的作用截然不同。
