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

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

Author information

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.

PMID:
31306410
PMCID:
PMC6657915
DOI:
10.1371/journal.pbio.3000072
[Indexed for MEDLINE]
Free PMC Article

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