当前位置: X-MOL 学术Genes. Immun. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Genomic profiling of T-cell activation suggests increased sensitivity of memory T cells to CD28 costimulation
Genes and Immunity ( IF 5 ) Pub Date : 2020-11-23 , DOI: 10.1038/s41435-020-00118-0
Dafni A Glinos 1, 2 , Blagoje Soskic 1, 3 , Cayman Williams 4 , Alan Kennedy 4 , Luke Jostins 5, 6, 7 , David M Sansom 4 , Gosia Trynka 1, 3
Affiliation  

T-cell activation is a critical driver of immune responses. The CD28 costimulation is an essential regulator of CD4 T-cell responses, however, its relative importance in naive and memory T cells is not fully understood. Using different model systems, we observe that human memory T cells are more sensitive to CD28 costimulation than naive T cells. To deconvolute how the T-cell receptor (TCR) and CD28 orchestrate activation of human T cells, we stimulate cells using varying intensities of TCR and CD28 and profiled gene expression. We show that genes involved in cell cycle progression and division are CD28-driven in memory cells, but under TCR control in naive cells. We further demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Using chromatin accessibility profiling, we observe that AP1 transcriptional regulation is enriched when both TCR and CD28 are engaged, whereas open chromatin near CD28-sensitive genes is enriched for NF-kB motifs. Lastly, we show that CD28-sensitive genes are enriched in GWAS regions associated with immune diseases, implicating a role for CD28 in disease development. Our study provides important insights into the differential role of costimulation in naive and memory T-cell responses and disease susceptibility.



中文翻译:

T 细胞激活的基因组分析表明记忆 T 细胞对 CD28 共刺激的敏感性增加

T 细胞活化是免疫反应的关键驱动因素。CD28 共刺激是 CD4 T 细胞反应的重要调节因子,然而,它在幼稚和记忆 T 细胞中的相对重要性尚不完全清楚。使用不同的模型系统,我们观察到人类记忆 T 细胞对 CD28 共刺激比幼稚 T 细胞更敏感。为了了解 T 细胞受体 (TCR) 和 CD28 如何协调人类 T 细胞的激活,我们使用不同强度的 TCR 和 CD28 以及基因表达谱来刺激细胞。我们表明,参与细胞周期进程和分裂的基因在记忆细胞中是 CD28 驱动的,但在幼稚细胞中受 TCR 控制。我们进一步证明 T 辅助细胞分化和细胞因子表达受 CD28 控制。使用染色质可及性分析,我们观察到,当 TCR 和 CD28 都参与时,AP1 转录调控得到丰富,而 CD28 敏感基因附近的开放染色质富含 NF-kB 基序。最后,我们表明 CD28 敏感基因在与免疫疾病相关的 GWAS 区域中富集,暗示 CD28 在疾病发展中的作用。我们的研究为共刺激在幼稚和记忆 T 细胞反应和疾病易感性中的不同作用提供了重要的见解。

更新日期:2020-11-23
down
wechat
bug