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

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.

淋巴组织T区成纤维网状细胞（FRCs）可主动促进T细胞迁移、稳态维持与增殖，同时亦可通过诱导型一氧化氮（NO）与组成型前列腺素类物质释放，抑制过度的T细胞应答。目前学界仍不清楚这类FRC衍生的介质通过何种机制减弱T细胞应答，且该过程是否可在体内发生。本研究证实，小鼠淋巴结（LN）FRCs能够以环氧合酶2（COX2）依赖且不依赖炎症的方式合成前列腺素E2（PGE2）。研究发现，该COX2/PGE2通路在强弱不同的T细胞应答中均处于激活状态，这与仅在强T细胞应答中才发挥作用的NO形成显著差异。已有研究表明，在体内慢性感染过程中，病毒特异性分化簇（CD）8细胞毒性T细胞上的PGE2受体信号可抑制T细胞存活与功能。本研究通过将COX2 flox/flox小鼠与在CC趋化因子配体19（CCL19）启动子调控下表达Cre重组酶（Cre recombinase）的CCL19cre小鼠杂交，最终明确CCL19+ FRCs是该COX2依赖性抑制因子的关键来源，提示淋巴组织内表达PGE2的FRCs可作为改善慢性感染期间T细胞介导的病原体清除效果的潜在治疗靶点。