Attenuation of chronic antiviral T-cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts

Karin Schaeuble; Hélène Cannelle; Stéphanie Favre; Hsin-Ying Huang; Susanne G Oberle; Daniel E Speiser; Dietmar Zehn; Sanjiv A Luther

doi:10.1371/journal.pbio.3000072

Attenuation of chronic antiviral T-cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts

PLoS Biol. 2019 Jul 15;17(7):e3000072. doi: 10.1371/journal.pbio.3000072. eCollection 2019 Jul.

Authors

Karin Schaeuble^{1

2}, Hélène Cannelle¹, Stéphanie Favre¹, Hsin-Ying Huang¹, Susanne G Oberle^{3

4}, Daniel E Speiser², Dietmar Zehn^{3

4

5}, Sanjiv A Luther¹

Affiliations

¹ Center for Immunity and Infection Lausanne, Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
² Department of Oncology, University of Lausanne and University Hospital, Epalinges, Switzerland.
³ Swiss Vaccine Research Institute, Epalinges, Switzerland.
⁴ Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
⁵ Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.

Abstract

Lymphoid T-zone fibroblastic reticular cells (FRCs) actively promote T-cell trafficking, homeostasis, and expansion but can also attenuate excessive T-cell responses via inducible nitric oxide (NO) and constitutive prostanoid release. It remains unclear how these FRC-derived mediators dampen T-cell responses and whether this occurs in vivo. Here, we confirm that murine lymph node (LN) FRCs produce prostaglandin E2 (PGE2) in a cyclooxygenase-2 (COX2)-dependent and inflammation-independent fashion. We show that this COX2/PGE2 pathway is active during both strong and weak T-cell responses, in contrast to NO, which only comes into play during strong T-cell responses. During chronic infections in vivo, PGE2-receptor signaling in virus-specific cluster of differentiation (CD)8 cytotoxic T cells was shown by others to suppress T-cell survival and function. Using COX2flox/flox mice crossed to mice expressing Cre recombinase expression under control of the CC chemokine ligand (CCL19) promoter (CCL19cre), we now identify CCL19+ FRC as the critical source of this COX2-dependent suppressive factor, suggesting PGE2-expressing FRCs within lymphoid tissues are an interesting therapeutic target to improve T-cell-mediated pathogen control during chronic infection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cell Movement / genetics
Cell Movement / immunology
Cell Proliferation / genetics
Cyclooxygenase 2 / genetics
Cyclooxygenase 2 / immunology*
Cyclooxygenase 2 / metabolism
Fibroblasts / immunology*
Fibroblasts / metabolism
Fibroblasts / virology
Lymph Nodes / cytology
Lymph Nodes / immunology*
Lymph Nodes / metabolism
Lymphocyte Activation / immunology
Lymphocytic Choriomeningitis / immunology
Lymphocytic Choriomeningitis / metabolism
Lymphocytic Choriomeningitis / virology
Lymphocytic choriomeningitis virus / immunology
Lymphocytic choriomeningitis virus / physiology
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Prostaglandins / biosynthesis
Prostaglandins / immunology*
T-Lymphocytes / immunology*
T-Lymphocytes / virology

Substances

Prostaglandins
Cyclooxygenase 2

Grants and funding

Swiss National Science Foundation (31003A-166161). Received by SAL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Novartis Foundation. Received by KS and SAL. The European Research Council (ProtecTC). Received by DZ. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.