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

Flavian D Brown; Debattama R Sen; Martin W LaFleur; Jernej Godec; Veronika Lukacs-Kornek; Frank A Schildberg; Hye-Jung Kim; Kathleen B Yates; Stéphane J H Ricoult; Kevin Bi; Justin D Trombley; Varun N Kapoor; Illana A Stanley; Viviana Cremasco; Nika N Danial; Brendan D Manning; Arlene H Sharpe; W Nicholas Haining; Shannon J Turley

doi:10.1038/s41590-019-0515-x

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

Nat Immunol. 2019 Dec;20(12):1668-1680. doi: 10.1038/s41590-019-0515-x. Epub 2019 Oct 21.

Authors

Flavian D Brown^{1

2

3

4

5

6}, Debattama R Sen^{1

2}, Martin W LaFleur^{1

2

3

4}, Jernej Godec^{1

2

3

4}, Veronika Lukacs-Kornek^{5

7}, Frank A Schildberg^{3

4

5

8}, Hye-Jung Kim^{3

5}, Kathleen B Yates^{2

9}, Stéphane J H Ricoult¹⁰, Kevin Bi^{2

9}, Justin D Trombley^{3

4}, Varun N Kapoor¹¹, Illana A Stanley^{12

13}, Viviana Cremasco^{5

14}, Nika N Danial^{12

13}, Brendan D Manning¹⁰, Arlene H Sharpe^{15

16

17

18}, W Nicholas Haining^{19

20

21

22}, Shannon J Turley^{23

24}

Affiliations

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. [email protected].
¹⁶ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. [email protected].
¹⁷ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
¹⁸ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
¹⁹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
²⁰ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
²¹ Division of Pediatric Hematology and Oncology, Children's Hospital, Boston, MA, USA. [email protected].
²² Merck Research Laboratories, Boston, MA, USA. [email protected].
²³ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
²⁴ Department of Cancer Immunology, Genentech, South San Francisco, CA, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology*
Cell Differentiation
Cell Proliferation
Cell Survival
Cells, Cultured
Cellular Reprogramming
Chromatin Assembly and Disassembly
Cytotoxicity, Immunologic
Epigenesis, Genetic
Fibroblasts / physiology*
Gene Expression Regulation
Immunologic Memory
Interleukin-6 / genetics
Interleukin-6 / metabolism
Lymph Nodes / immunology*
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide / metabolism

Substances

Interleukin-6
Nitric Oxide

Abstract

Publication types

MeSH terms

Substances

Grants and funding