Raberger Julia, Schebesta Alexandra, Sakaguchi Shinya, Boucheron Nicole, Blomberg K Emelie M, Berglöf Anna, Kolbe Thomas, Smith C I Edvard, Rülicke Thomas, Ellmeier Wilfried
Division of Immunobiology, Institute of Immunology, Center for Physiology, Pathophysiology and Immunology, Medical University of Vienna, A-1090 Vienna, Austria.
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17919-24. doi: 10.1073/pnas.0805733105. Epub 2008 Nov 12.
Transcriptional pathways controlling the development of CD44(hi) memory phenotype (MP) T cells with "innate-like" functions are not well understood. Here we show that the BTB (bric-a-brac, tramtrack, broad complex) domain-containing protein promyelocytic leukemia zinc finger (PLZF) is expressed in CD44(hi), but not in CD44(lo), CD4(+) T cells. Transgenic expression of PLZF during T cell development and in CD4(+) and CD8(+) T cells induced a T cell intrinsic program leading to an increase in peripheral CD44(hi) MP CD4(+) and CD8(+) T cells and a corresponding decrease of naïve CD44(lo) T cells. The MP CD4(+) and CD8(+) T cells produced IFNgamma upon PMA/ionomycin stimulation, thus showing innate-like function. Changes in the naïve versus memory-like subset distribution were already evident in single-positive thymocytes, indicating PLZF-induced T cell developmental alterations. In addition, CD1d-restricted natural killer T cells in PLZF transgenic mice showed impaired development and were severely reduced in the periphery. Finally, after anti-CD3/CD28 stimulation, CD4(+) transgenic T cells showed reduced IL-2 and IFNgamma production but increased IL-4 secretion as a result of enhanced IL-4 production of the CD44(hi)CD62L(+) subset. Our data indicate that PLZF is a novel regulator of the development of CD44(hi) MP T cells with a characteristic partial innate-like phenotype.
控制具有“类天然”功能的CD44高表达记忆表型（MP）T细胞发育的转录途径尚未完全清楚。在此我们表明，含BTB（bric-a-brac、tramtrack、broad complex）结构域的蛋白早幼粒细胞白血病锌指蛋白（PLZF）在CD44高表达的CD4⁺ T细胞中表达，但在CD44低表达的细胞中不表达。在T细胞发育过程中以及在CD4⁺和CD8⁺ T细胞中转基因表达PLZF诱导了一个T细胞内在程序，导致外周CD44高表达的MP CD4⁺和CD8⁺ T细胞增加，而幼稚CD44低表达的T细胞相应减少。MP CD4⁺和CD8⁺ T细胞在佛波酯/离子霉素刺激下产生γ干扰素，从而显示出类天然功能。幼稚与记忆样亚群分布的变化在单阳性胸腺细胞中已经很明显，表明PLZF诱导了T细胞发育改变。此外，PLZF转基因小鼠中受CD1d限制的自然杀伤T细胞显示发育受损，在外周严重减少。最后，抗CD3/CD28刺激后，CD4⁺转基因T细胞由于CD44高表达CD62L⁺亚群IL-4产生增加，IL-2和γ干扰素产生减少，但IL-4分泌增加。我们的数据表明，PLZF是具有特征性部分类天然表型的CD44高表达MP T细胞发育的新型调节因子。
