Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity.
Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity.
复制标题
DOI：
10.1016/j.cell.2015.11.009
复制
发表时间：
2015-12-03
期刊：
影响因子：
64.5
通讯作者：
Regev A
中科院分区：
文献类型：
--
作者：
Gaublomme JT;Yosef N;Lee Y;Gertner RS;Yang LV;Wu C;Pandolfi PP;Mak T;Satija R;Shalek AK;Kuchroo VK;Park H;Regev A
广泛的细胞异质性存在于被归类为单一谱系的特定免疫细胞亚型内，但其分子基础很少在基因组规模上表征。在这里，我们使用单细胞RNA-seq来研究在自身免疫性脑脊髓炎（EAE）的高峰期从中枢神经系统（CNS）和淋巴结（LN）分离的Th 17细胞的异质性和致病性的分子机制，或者在致病性或非致病性极化条件下体外分化。计算分析涉及一系列的细胞状态在体内体外分化的Th 17细胞，并揭示了基因的致病性和疾病的易感性。使用敲除小鼠，我们验证了四个新基因：Gpr 65，Plzp，Toso和Cd 5l（在配套论文中）。因此，细胞异质性告知Th 17在自身免疫中的功能，并且可以鉴定用于选择性抑制致病性Th 17细胞的靶标，同时潜在地保留非致病性组织保护性细胞。
Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or differentiated in vitro under either pathogenic or non-pathogenic polarization conditions. Computational analysis relates a spectrum of cellular states in vivo to in vitro differentiated Th17 cells, and unveils genes governing pathogenicity and disease susceptibility. Using knockout mice, we validate four new genes: Gpr65, Plzp, Toso and Cd5l (in a companion paper). Cellular heterogeneity thus informs Th17 function in autoimmunity, and can identify targets for selective suppression of pathogenic Th17 cells while potentially sparing non-pathogenic tissue-protective ones.