Wu Zuopeng, Jia Xinying, de la Cruz Laura, Su Xun-Cheng, Marzolf Bruz, Troisch Pamela, Zak Daniel, Hamilton Adam, Whittle Belinda, Yu Di, Sheahan Daniel, Bertram Edward, Aderem Alan, Otting Gottfried, Goodnow Christopher C, Hoyne Gerard F
John Curtin School of Medical Research, Australian Phenomics Facility, Australian National University, Canberra ACT 0200, Australia.
Immunity. 2008 Dec 19;29(6):863-75. doi: 10.1016/j.immuni.2008.11.004.
Differentiation of memory cells involves DNA-sequence changes in B lymphocytes but is less clearly defined in T cells. RNA rearrangement is identified here as a key event in memory T cell differentiation by analysis of a mouse mutation that altered the proportions of naive and memory T cells and crippled the process of Ptprc exon silencing needed to generate CD45RO in memory T cells. A single substitution in a memory-induced RNA-binding protein, hnRNPLL, destabilized an RNA-recognition domain that bound with micromolar affinity to RNA containing the Ptprc exon-silencing sequence. Hnrpll mutation selectively diminished T cell accumulation in peripheral lymphoid tissues but not proliferation. Exon-array analysis of Hnrpll mutant naive and memory T cells revealed an extensive program of alternative mRNA splicing in memory T cells, coordinated by hnRNPLL. A remarkable overlap with alternative splicing in neural tissues may reflect a co-opted strategy for diversifying memory T cells.
记忆细胞的分化涉及B淋巴细胞中的DNA序列变化，但在T细胞中定义不太明确。通过分析一种小鼠突变，RNA重排被确定为记忆性T细胞分化中的关键事件，该突变改变了初始T细胞和记忆T细胞的比例，并破坏了记忆T细胞中产生CD45RO所需的Ptprc外显子沉默过程。记忆诱导的RNA结合蛋白hnRNPLL中的单个取代使一个RNA识别结构域不稳定，该结构域以微摩尔亲和力与含有Ptprc外显子沉默序列的RNA结合。Hnrpll突变选择性地减少了外周淋巴组织中T细胞的积累，但不影响其增殖。对Hnrpll突变的初始T细胞和记忆T细胞进行外显子阵列分析发现，记忆T细胞中存在由hnRNPLL协调的广泛的可变mRNA剪接程序。与神经组织中可变剪接的显著重叠可能反映了一种用于使记忆T细胞多样化的共同策略。
