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

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 +...

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Bibliographic Details
Published in:Nature immunology Vol. 20; no. 12; pp. 1668 - 1680
Main Authors: Brown, Flavian D., Sen, Debattama R., LaFleur, Martin W., Godec, Jernej, Lukacs-Kornek, Veronika, Schildberg, Frank A., Kim, Hye-Jung, Yates, Kathleen B., Ricoult, Stéphane J. H., Bi, Kevin, Trombley, Justin D., Kapoor, Varun N., Stanley, Illana A., Cremasco, Viviana, Danial, Nika N., Manning, Brendan D., Sharpe, Arlene H., Haining, W. Nicholas, Turley, Shannon J.
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.12.2019
Nature Publishing Group
Subjects:
631/1647
631/250
Animals
Biomedical and Life Sciences
Biomedicine
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
Cell Differentiation
Cell Proliferation
Cell Survival
Cells, Cultured
Cellular Reprogramming
Chromatin
Chromatin Assembly and Disassembly
Cytotoxicity, Immunologic
Epigenesis, Genetic
Epigenetic inheritance
Epigenetics
Fibroblasts - physiology
Gene Expression Regulation
Immunologic Memory
Immunological memory
Immunology
Infectious Diseases
Interleukin 6
Interleukin-6 - genetics
Interleukin-6 - metabolism
Interleukins
Lymph nodes
Lymph Nodes - immunology
Lymphocyte Activation
Lymphocytes
Lymphocytes T
Lymphoid tissue
Memory cells
Mice
Mice, Inbred C57BL
Mice, Knockout
Nitric oxide
Nitric Oxide - metabolism
T cells
Massachusetts
ISSN:1529-2908, 1529-2916, 1529-2916
Online Access:Get full text
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Description
Summary: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. Fibroblastic reticular cells (FRCs) are dynamic regulators of lymphoid tissue structure. Turley and colleagues show FRCs also support activated T cells by producing IL-6, which confers an advantage to CD8+ T cell memory responses.
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F.D.B. conceived and conducted most of the experiments, analyzed and interpreted data and wrote the manuscript. D.R.S. conducted experiments and analyzed and interpreted data. J.G., M.W.L., V.L.-K., F.A.S., H-J.K., K.B.Y., S.J.H.R., K.B. and V.N.K. conducted experiments and interpreted data. J.D.T. and I.A.S. discussed data and provided technical assistance. V.C., N.N.D. and B.D.M. discussed and interpreted data. A.H.S., W.N.H. and S.J.T. directed the study, analyzed and interpreted results and wrote the manuscript.
Author contributions
ISSN:1529-2908
1529-2916
1529-2916
DOI:10.1038/s41590-019-0515-x