Gil M Pilar, Salomon Rachelle, Louten Jennifer, Biron Christine A
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
Blood. 2006 Feb 1;107(3):987-93. doi: 10.1182/blood-2005-07-2834. Epub 2005 Oct 6.
Type 1 interferons (IFNs) are induced in vivo, administered therapeutically, and potential targets for amelioration of autoimmune diseases. The cytokines mediate profound antiproliferative effects. Signal transducer and activator of transcription 1 (STAT1)-dependent signaling pathways are required for inhibition of proliferation, and viral infections can elicit high levels of type 1 IFNs as well as total STAT1 protein expression. Thus, a mechanism must be in place to help antigen-specific T cells overcome IFN-induced inhibition of proliferation. The studies reported here demonstrate that total CD8 T-cell proliferation in the presence of IFNs, ex vivo in response to cytokines and in vivo during viral infection, is inhibited through a STAT1-dependent mechanism. In contrast, major proportions of antigen-specific CD8, but not CD4, T cells are rendered less sensitive to this inhibition, express lower endogenous levels of total STAT1, and are selectively proliferating in the presence of type 1 IFN, at key times after viral challenge. Taken together, these novel results show that differential STAT1 expression is used by the immune system to modify cytokine-mediated effects on T-cell expansion and have implications for the consequences of therapeutic intervention in cytokine function.
1型干扰素（IFNs）在体内可被诱导产生，用于治疗给药，是自身免疫性疾病改善的潜在靶点。这些细胞因子介导深刻的抗增殖作用。抑制增殖需要信号转导和转录激活因子1（STAT1）依赖的信号通路，病毒感染可引发高水平的1型干扰素以及总的STAT1蛋白表达。因此，必须存在一种机制来帮助抗原特异性T细胞克服干扰素诱导的增殖抑制。本文报道的研究表明，在干扰素存在的情况下，体外对细胞因子的反应以及病毒感染期间体内总的CD8 T细胞增殖通过STAT1依赖的机制受到抑制。相比之下，大部分抗原特异性CD8 T细胞（而非CD4 T细胞）对这种抑制的敏感性较低，总的STAT1内源性表达水平较低，并且在病毒攻击后的关键时间点，在1型干扰素存在的情况下选择性增殖。综上所述，这些新结果表明免疫系统利用STAT1的差异表达来改变细胞因子介导的对T细胞扩增的影响，并对细胞因子功能的治疗干预后果具有启示意义。
