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

• Published in: PLoS biology 2019-07, Vol.17 (7), p.e3000072-e3000072
• Main Authors: Schaeuble, Karin, Cannelle, Hélène, Favre, Stéphanie, Huang, Hsin-Ying, Oberle, Susanne G, Speiser, Daniel E, Zehn, Dietmar, Luther, Sanjiv A
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Attenuation; Biochemistry; Biology and Life Sciences; Biosynthesis; Cancer; CCL19 protein; Cell differentiation; Cell Line; Cell Movement - genetics; Cell Movement - immunology; Cell Proliferation - genetics; Cell survival; Chemokines; Chronic infection; Cre recombinase; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - immunology; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Cytotoxicity; Enzymes; Fibroblasts; Fibroblasts - immunology; Fibroblasts - metabolism; Fibroblasts - virology; Flox; Funding; Homeostasis; Immunology; Infections; Inflammation; Lipids; Lymph nodes; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymphatic system; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - metabolism; Lymphocytic Choriomeningitis - virology; Lymphocytic choriomeningitis virus - immunology; Lymphocytic choriomeningitis virus - physiology; Lymphoid tissue; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nitric oxide; Nonsteroidal anti-inflammatory drugs; Observations; Oncology; Physiological aspects; Prostaglandin E2; Prostaglandins - biosynthesis; Prostaglandins - immunology; Prostanoids; Recombinase; Research and Analysis Methods; Short Reports; T cell receptors; T cells; T-Lymphocytes - immunology; T-Lymphocytes - virology; Therapeutic applications; Viruses
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000072

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.