Luetke-Eversloh Merlin, Hammer Quirin, Durek Pawel, Nordström Karl, Gasparoni Gilles, Pink Matthias, Hamann Alf, Walter Jörn, Chang Hyun-Dong, Dong Jun, Romagnani Chiara
Innate Immunity, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, Berlin, Germany.
Experimental Rheumatology, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, Berlin, Germany; Cell Biology, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, Berlin, Germany.
PLoS Pathog. 2014 Oct 16;10(10):e1004441. doi: 10.1371/journal.ppat.1004441. eCollection 2014 Oct.
Memory type 1 T helper (T(H)1) cells are characterized by the stable expression of interferon (IFN)-γ as well as by the epigenetic imprinting of the IFNG locus. Among innate cells, NK cells play a crucial role in the defense against cytomegalovirus (CMV) and represent the main source of IFN-γ. Recently, it was shown that memory-like features can be observed in NK cell subsets after CMV infection. However, the molecular mechanisms underlying NK cell adaptive properties have not been completely defined. In the present study, we demonstrated that only NKG2Chi NK cells expanded in human CMV (HCMV) seropositive individuals underwent epigenetic remodeling of the IFNG conserved non-coding sequence (CNS) 1, similar to memory CD8(+) T cells or T(H)1 cells. The accessibility of the CNS1 was required to enhance IFN-γ transcriptional activity in response to NKG2C and 2B4 engagement, which led to consistent IFN-γ production in NKG2C(hi) NK cells. Thus, our data identify epigenetic imprinting of the IFNG locus as selective hallmark and crucial mechanism driving strong and stable IFN-γ expression in HCMV-specific NK cell expansions, providing a molecular basis for the regulation of adaptive features in innate cells.
1型记忆性辅助性T细胞（T(H)1）的特征在于干扰素（IFN）-γ的稳定表达以及IFNG基因座的表观遗传印记。在先天性细胞中，自然杀伤细胞（NK细胞）在抵抗巨细胞病毒（CMV）的防御中起关键作用，并且是IFN-γ的主要来源。最近的研究表明，CMV感染后在NK细胞亚群中可观察到类似记忆的特征。然而，NK细胞适应性特性的分子机制尚未完全明确。在本研究中，我们证明，只有在人巨细胞病毒（HCMV）血清阳性个体中扩增的NKG2Chi NK细胞经历了IFNG保守非编码序列（CNS）1的表观遗传重塑，这类似于记忆性CD8(+) T细胞或T(H)1细胞。CNS1的可及性是增强IFN-γ转录活性以响应NKG2C和2B4参与所必需的，这导致NKG2C(hi) NK细胞中持续产生IFN-γ。因此，我们的数据确定IFNG基因座的表观遗传印记是HCMV特异性NK细胞扩增中驱动强大而稳定的IFN-γ表达的选择性标志和关键机制，为先天性细胞中适应性特征的调节提供了分子基础。
