Churilla A M, Braciale T J, Braciale V L
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110.
J Exp Med. 1989 Jul 1;170(1):105-21. doi: 10.1084/jem.170.1.105.
We previously reported that with time, after antigenic stimulation of antigen-regulated murine T lymphocyte clones, total IL-2-R expression decayed 10-50-fold, commensurate with a decline in the ability of the cells to proliferate to IL-2. However, late after antigenic stimulation, when the cells were refractory to the IL-2-proliferative stimulus, high levels of high affinity IL-2-R remained. In this report we further explore the basis of unresponsiveness to IL-2 in the quiescent clones. We show that the proto-oncogene c-myc is induced in the late cell population by IL-2 to comparable levels observed early after antigen stimulation. IL-2-dependent c-myb induction, however, is seen only early after activation but not in the late-activated population. Analysis of the IL-2-dependent expression of c-myb mRNA with time after antigenic stimulation showed that steadystate c-myb expression declines dramatically with kinetics closely paralleling a decay in IL-2-dependent proliferative ability. In contrast, steadystate c-myc expression remains high throughout this period. Expression of c-myb is critical for proliferation of these cells since antisense oligodeoxy-nucleotide to c-myb can inhibit their IL-2-dependent proliferation. We present evidence for a pathway of c-myb induction via the TCR that is independent of the IL-2/IL-2-R interaction. In addition, the inhibition of IL-2-R-induced c-myb expression by 2-aminopurine and enhanced induction of c-myb via the TCR demonstrate that TCR activation and IL-2-R activation lead to induction of c-myb by different mechanisms.
我们先前报道过，在对抗原调节的小鼠T淋巴细胞克隆进行抗原刺激后，随着时间推移，总IL-2-R表达下降了10至50倍，这与细胞对IL-2增殖能力的下降相一致。然而，在抗原刺激后期，当细胞对IL-2增殖刺激产生耐受时，仍存在高水平的高亲和力IL-2-R。在本报告中，我们进一步探究了静止克隆中对IL-2无反应性的基础。我们发现，原癌基因c-myc在后期细胞群体中被IL-2诱导至抗原刺激后早期所观察到的可比水平。然而，IL-2依赖性c-myb诱导仅在激活早期出现，而在后期激活群体中未观察到。对抗原刺激后不同时间点c-myb mRNA的IL-2依赖性表达分析表明，c-myb的稳态表达急剧下降，其动力学与IL-2依赖性增殖能力的衰减密切平行。相比之下，在此期间c-myc的稳态表达一直保持在较高水平。c-myb的表达对这些细胞的增殖至关重要，因为针对c-myb的反义寡脱氧核苷酸可抑制其IL-2依赖性增殖。我们提供了证据表明存在一条通过TCR诱导c-myb的途径，该途径独立于IL-2/IL-2-R相互作用。此外，2-氨基嘌呤对IL-2-R诱导的c-myb表达的抑制以及通过TCR对c-myb诱导的增强表明，TCR激活和IL-2-R激活通过不同机制导致c-myb的诱导。
