한빛사논문
- 조회2,547
Rohit R. Jadhava,b,1, Se Jin Imc,1, Bin Hua,b,1, Masao Hashimotoc, Peng Lid, Jian-Xin Lind, Warren J. Leonardd, William J. Greenleafe,f,g, Rafi Ahmedc,2, and Jorg J. Goronzya,b,2
a Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA 94305; b Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA 94306; c Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; d Laboratory of Molecular Immunology, Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; e Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305; f Department of Genetics, Stanford University, Stanford, CA 94305; and g Department of Applied Physics, Stanford University, Stanford, CA 94305
1 R.R.J., S.J.I., and B.H. contributed equally to this work.
2 To whom correspondence may be addressed.
Abstract
We have recently defined a novel population of PD-1 (programmed cell death 1)+ TCF1 (T cell factor 1)+ virus-specific CD8 T cells that function as resource cells during chronic LCMV infection and provide the proliferative burst seen after PD-1 blockade. Such CD8 T cells have been found in other chronic infections and also in cancer in mice and humans. These CD8 T cells exhibit stem-like properties undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells. Here we compared the epigenetic signature of stem-like CD8 T cells with exhausted CD8 T cells. ATAC-seq analysis showed that stem-like CD8 T cells had a unique signature implicating activity of HMG (TCF) and RHD (NF-κB) transcription factor family members in contrast to higher accessibility to ETS and RUNX motifs in exhausted CD8 T cells. In addition, regulatory regions of the transcription factors Tcf7 and Id3 were more accessible in stem-like cells whereas Prdm1 and Id2 were more accessible in exhausted CD8 T cells. We also compared the epigenetic signatures of the 2 CD8 T cell subsets from chronically infected mice with effector and memory CD8 T cells generated after an acute LCMV infection. Both CD8 T cell subsets generated during chronic infection were strikingly different from CD8 T cell subsets from acute infection. Interestingly, the stem-like CD8 T cell subset from chronic infection, despite sharing key functional properties with memory CD8 T cells, had a very distinct epigenetic program. These results show that the chronic stem-like CD8 T cell program represents a specific adaptation of the T cell response to persistent antigenic stimulation.
CD8 T cell exhaustion, ATAC-seq, epigenetic profiles
논문정보
- Research article
- 2019년 07월 (BRIC 등록일 2019-07-16)
- 국외 연구진
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