Genomic profiling of T-cell activation suggests increased sensitivity of memory T cells to CD28 costimulation

被引:18
|
作者
Glinos, Dafni A. [1 ,2 ]
Soskic, Blagoje [1 ,3 ]
Williams, Cayman [4 ]
Kennedy, Alan [4 ]
Jostins, Luke [5 ,6 ,7 ]
Sansom, David M. [4 ]
Trynka, Gosia [1 ,3 ]
机构
[1] Wellcome Sanger Inst, Wellcome Genome Campus, Hinxton CB10 1SA, England
[2] New York Genome Ctr, New York, NY 10013 USA
[3] Open Targets, Wellcome Genome Campus, Hinxton CB10 1SA, England
[4] Royal Free Hosp, UCL Inst Immun & Transplantat, London OX3 7FY, England
[5] Univ Oxford, Kennedy Inst Rheumatol, Roosevelt Dr, Oxford OX3 7FY, England
[6] Univ Oxford, Big Data Inst, Roosevelt Dr, Oxford OX3 7FZ, England
[7] Univ Oxford Christ Church, St Aldates, Oxford OX1 1DP, England
基金
英国惠康基金;
关键词
MULTIORGAN TISSUE DESTRUCTION; IMMUNE DYSREGULATION; AUTOIMMUNE-DISEASE; MULTIPLE COMMON; MOLECULAR-BASIS; KAPPA-B; VARIANTS; CTLA-4; INDUCTION; TARGET;
D O I
10.1038/s41435-020-00118-0
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:390 / 408
页数:19
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