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Nat Immunol. 2019 Oct 21. doi: 10.1038/s41590-019-0515-x. [Epub ahead of print]

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

Brown FD1,2,3,4,5,6, Sen DR1,2, LaFleur MW1,2,3,4, Godec J1,2,3,4, Lukacs-Kornek V5,7, Schildberg FA3,4,5,8, Kim HJ3,5, Yates KB2,9, Ricoult SJH10, Bi K2,9, Trombley JD3,4, Kapoor VN11, Stanley IA12,13, Cremasco V5,14, Danial NN12,13, Manning BD10, Sharpe AH15,16,17,18, Haining WN19,20,21,22, Turley SJ23,24.

Author information

1
Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
4
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
5
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
6
Neon Therapeutics Inc., Cambridge, MA, USA.
7
Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
8
Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany.
9
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
10
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
11
Department of Cancer Immunology, Genentech, South San Francisco, CA, USA.
12
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
13
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
14
Immuno-Oncology, Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
15
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. arlene_sharpe@hms.harvard.edu.
16
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. arlene_sharpe@hms.harvard.edu.
17
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. arlene_sharpe@hms.harvard.edu.
18
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. arlene_sharpe@hms.harvard.edu.
19
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. nick.haining@merck.com.
20
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. nick.haining@merck.com.
21
Division of Pediatric Hematology and Oncology, Children's Hospital, Boston, MA, USA. nick.haining@merck.com.
22
Merck Research Laboratories, Boston, MA, USA. nick.haining@merck.com.
23
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. turley.shannon@gene.com.
24
Department of Cancer Immunology, Genentech, South San Francisco, CA, USA. turley.shannon@gene.com.

Abstract

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.

PMID:
31636464
DOI:
10.1038/s41590-019-0515-x

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