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.

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

Grant support

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.