Open AccessAttenuation of chronic antiviral T-cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts
Author(s) -
Karin Schaeuble,
Hélène Cannelle,
Stéphanie Favre,
Hsiao-Yun Huang,
Susanne Oberle,
Daniel E. Speiser,
Dietmar Zehn,
Sanjiv A. Luther
Publication year - 2019
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3000072
Subject(s) - biology , ccl19 , prostanoid , t cell , microbiology and biotechnology , immunology , cytotoxic t cell , chemokine , cancer research , inflammation , chemokine receptor , prostaglandin , in vitro , endocrinology , immune system , biochemistry
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 E 2 (PGE 2 ) in a cyclooxygenase-2 (COX2)-dependent and inflammation-independent fashion. We show that this COX2/PGE 2 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, PGE 2 -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 COX2 flox/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 PGE 2 -expressing FRCs within lymphoid tissues are an interesting therapeutic target to improve T-cell–mediated pathogen control during chronic infection.