Baseta J G, Stutman O
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J Immunol. 2000 Nov 15;165(10):5621-30. doi: 10.4049/jimmunol.165.10.5621.
TNF is a proinflammatory cytokine with opposing death/no-death effects in vivo and in vitro. Our studies showed that TNF regulates mouse thymocyte production, inducing both apoptosis and proliferation of the most immature CD3(-)CD4(-)CD8(-) triple negative (TN) subset within a broad range of dosages (10(1)-10(5) pg/ml) in the presence of IL-7. TNF apoptosis affected only the TN3 (CD44(-)CD25(+)) and TN4 (CD44(-)CD25(-)) subsets that expressed both TNFR-p55 and -p75. Although each TNFR alone could mediate TNF apoptosis, maximal apoptosis was seen in C57BL/6J wild type, which expressed both TNFRs. TNF also induced proliferation of TN3 cells at higher doses (10(4)-10(5) pg/ml) mediated only by TNFR-p75. Both anti-TNFR-p55 and -TNFR-p75 mAb inhibited apoptosis but only anti-p75 inhibited proliferation. TNF also regulated TN proliferation to IL-7 because TNFR knockout (KO), TNF KO, and TNF/lymphotoxin alpha and beta triple KO mice showed 2- to 3-fold increased responses not seen in C57BL/6J wild type. In vivo, TNFR KO mice showed thymic hypertrophy with a 60% increase in total thymocytes, with no effect on the CD4/CD8 subsets. We conclude that TNF maintains homeostatic control of total thymocyte production by negative selection of TN3 and TN4 prothymocytes and down-regulation of their proliferation to endogenous IL-7.
肿瘤坏死因子（TNF）是一种促炎细胞因子，在体内和体外具有相反的死亡/无死亡效应。我们的研究表明，在白细胞介素-7（IL-7）存在的情况下，TNF在广泛的剂量范围（10¹-10⁵ pg/ml）内调节小鼠胸腺细胞的产生，诱导最不成熟的CD3⁻CD4⁻CD8⁻三阴性（TN）亚群发生凋亡和增殖。TNF诱导的凋亡仅影响同时表达TNFR-p55和-p75的TN3（CD44⁻CD25⁺）和TN4（CD44⁻CD25⁻）亚群。虽然单独每个TNFR都可以介导TNF诱导的凋亡，但在同时表达两种TNFR的C57BL/6J野生型小鼠中观察到最大程度的凋亡。TNF还在较高剂量（10⁴-10⁵ pg/ml）时诱导TN3细胞增殖，这仅由TNFR-p75介导。抗TNFR-p55和抗TNFR-p75单克隆抗体均抑制凋亡，但只有抗p75抑制增殖。TNF还调节TN对IL-7的增殖反应，因为TNFR基因敲除（KO）小鼠、TNF KO小鼠以及TNF/淋巴毒素α和β三联KO小鼠表现出比C57BL/6J野生型小鼠高2至3倍的反应，而野生型小鼠未出现这种情况。在体内，TNFR KO小鼠表现出胸腺肥大，总胸腺细胞增加60%，对CD4/CD8亚群没有影响。我们得出结论，TNF通过对TN3和TN4原胸腺细胞的阴性选择以及下调它们对内源性IL-7的增殖反应，维持胸腺细胞总产生量的稳态控制。
