Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling

被引:62
作者
Brown, Flavian D. [1 ,2 ,3 ,4 ,5 ,6 ,14 ]
Sen, Debattama R. [1 ,2 ]
LaFleur, Martin W. [1 ,2 ,3 ,4 ,5 ]
Godec, Jernej [1 ,2 ,3 ,4 ,5 ]
Lukacs-Kornek, Veronika [6 ,15 ]
Schildberg, Frank A. [3 ,4 ,5 ,6 ,16 ]
Kim, Hye-Jung [3 ,6 ]
Yates, Kathleen B. [7 ]
Ricoult, Stephane J. H. [8 ]
Bi, Kevin [7 ]
Trombley, Justin D. [3 ,4 ,5 ]
Kapoor, Varun N. [9 ]
Stanley, Illana A. [10 ,11 ]
Cremasco, Viviana [6 ,17 ]
Danial, Nika N. [10 ,11 ]
Manning, Brendan D. [8 ]
Sharpe, Arlene H. [3 ,4 ,5 ,7 ,12 ]
Haining, W. Nicholas [2 ,7 ,13 ,18 ]
Turley, Shannon J. [6 ,9 ]
机构
[1] Harvard Med Sch, Div Med Sci, Boston, MA 02115 USA
[2] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA
[3] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA
[4] Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA
[5] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA
[6] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA USA
[7] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA
[8] Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA USA
[9] Dept Canc Immunol Genentech, South San Francisco, CA USA
[10] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA
[11] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA
[12] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA
[13] Childrens Hosp, Div Pediat Hematol & Oncol, 300 Longwood Ave, Boston, MA 02115 USA
[14] Neon Therapeut Inc, Cambridge, MA USA
[15] Rhein Friedrich Wilhelms Univ Bonn, Inst Expt Immunol, Bonn, Germany
[16] Univ Hosp Bonn, Clin Orthoped & Trauma Surg, Bonn, Germany
[17] Novartis Inst BioMed Res, Immunooncol, Cambridge, MA USA
[18] Merck Res Labs, Boston, MA USA
基金
美国国家卫生研究院;
关键词
LYMPH-NODE; NITRIC-OXIDE; DENDRITIC CELLS; STROMAL CELLS; CHROMATIN; IMMUNE; DIFFERENTIATION; HOMEOSTASIS; MIGRATION; GENE;
D O I
10.1038/s41590-019-0515-x
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Lymph node fibroblastic reticular cells (FRCs) respond to signals from activated T cells by releasing nitric oxide, which inhibits T cell proliferation and restricts the size of the expanding T cell pool. Whether interactions with FRCs also support the function or differentiation of activated CD8(+) T cells is not known. Here we report that encounters with FRCs enhanced cytokine production and remodeled chromatin accessibility in newly activated CD8(+) T cells via interleukin-6. These epigenetic changes facilitated metabolic reprogramming and amplified the activity of pro-survival pathways through differential transcription factor activity. Accordingly, FRC conditioning significantly enhanced the persistence of virus-specific CD8(+) T cells in vivo and augmented their differentiation into tissue-resident memory T cells. Our study demonstrates that FRCs play a role beyond restricting T cell expansion-they can also shape the fate and function of CD8(+) T cells.
引用
收藏
页码:1668 / +
页数:15
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