Muta H, Boise L H, Fang L, Podack E R
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33136, USA.
J Immunol. 2000 Nov 1;165(9):5105-11. doi: 10.4049/jimmunol.165.9.5105.
Although CD30 has long been recognized as an important marker on many lymphomas of diverse origin and as activation molecule on B cells and T cells, its primary function has remained obscure. We now report that CD30 signals may serve to inhibit effector cell activity by integrating gene expression changes of several pathways important for cytotoxic NK and T cell effector function. In the large granular lymphoma line YT, CD30 signals down-regulate the expression of cytotoxic effector molecules, Fas ligand, perforin, granzyme B, and abrogate cytotoxicity. c-myc, a regulator of proliferation and an upstream regulator of Fas ligand expression, is completely suppressed by CD30. Furthermore, CD30 signals strongly induce CCR7, suggesting a role for CD30 signals in the homing of lymphocytes to lymph nodes. The up-regulation of Fas, death receptor 3, and TNF-related apoptosis-inducing ligand by CD30 indicates an increase in susceptibility to apoptotic signals whereas up-regulation of TNFR-associated factor 1 and cellular inhibitor of apoptosis 2 protect cells from certain types of apoptosis. Using gene microarrays, 750 gene products were induced and 90 gene products were suppressed >2-fold by CD30 signals. Signals emanating from CD30 use both TNFR-associated factor 2-dependent and -independent pathways. The integration of CD30 signals in a lymphoma line suggests that CD30 can down-modulate lymphocyte effector function and proliferation while directing the cells to lymph nodes and increasing their susceptibility to certain apoptotic signals. These studies may provide a molecular mechanism for the recently observed CD30-mediated suppression of CTL activity in vivo in a diabetes model.
尽管CD30长期以来一直被认为是多种起源的淋巴瘤的重要标志物以及B细胞和T细胞上的激活分子，但其主要功能仍不清楚。我们现在报告，CD30信号可能通过整合对细胞毒性NK和T细胞效应功能重要的几种途径的基因表达变化来抑制效应细胞活性。在大颗粒淋巴瘤细胞系YT中，CD30信号下调细胞毒性效应分子、Fas配体、穿孔素、颗粒酶B的表达，并消除细胞毒性。c-myc是一种增殖调节因子，也是Fas配体表达的上游调节因子，被CD30完全抑制。此外，CD30信号强烈诱导CCR7，表明CD30信号在淋巴细胞归巢至淋巴结中起作用。CD30对Fas、死亡受体3和肿瘤坏死因子相关凋亡诱导配体的上调表明对凋亡信号的敏感性增加，而肿瘤坏死因子受体相关因子1和细胞凋亡抑制因子2的上调则保护细胞免受某些类型的凋亡。使用基因微阵列，750种基因产物被CD30信号诱导，90种基因产物被抑制超过2倍。来自CD30的信号使用肿瘤坏死因子受体相关因子2依赖性和非依赖性途径。淋巴瘤细胞系中CD30信号的整合表明，CD30可以下调淋巴细胞效应功能和增殖，同时将细胞导向淋巴结并增加它们对某些凋亡信号的敏感性。这些研究可能为最近在糖尿病模型中观察到的CD30介导的体内CTL活性抑制提供分子机制。
