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

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

doi:10.1371/journal.pbio.3000072

Avinash Bhandoola, Karin Schaeuble + Show 7 more

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https://doi.org/10.1371/journal.pbio.3000072

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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.

Highlights

Lymph nodes (LNs) are secondary lymphoid organs (SLOs) specialized in filtering lymph fluid and initiating T- and B-cell responses to foreign antigens
To exclude a role for dendritic cell (DC) as a source of COX-dependent prostanoids and to study the role of COX2 in fibroblastic reticular cell (FRC), we activated naïve murine T cells using α cluster of differentiation (CD)3/ 28-coated beads in the presence or absence of the FRC line called peripheral LN2
We show that FRC lines and ex vivo FRC display a highly active COX2/ prostaglandin E2 (PGE2) pathway that dampens the expansion of in vitro-activated CD8 and CD4 T cells by acting via EP2/4 receptors

Summary

Introduction

Lymph nodes (LNs) are secondary lymphoid organs (SLOs) specialized in filtering lymph fluid and initiating T- and B-cell responses to foreign antigens. Antigen-specific T cells are selected to expand and differentiate into effector cells by dendritic cells (DCs) that present processed antigen in the context of major histocompatibility complex (MHC) and costimulatory signals. Attenuation of T-cell response by COX2+ lymph node fibroblasts (ProtecTC). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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