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T区成纤维网状细胞（Lymphoid T-zone fibroblastic reticular cells, FRCs）可主动促进T细胞趋化、稳态维持与增殖，同时亦可通过诱导型一氧化氮（inducible nitric oxide, NO）与组成型前列腺素类介质释放，抑制过度的T细胞应答。目前尚不明确这些FRC衍生的介质如何削弱T细胞应答，且该过程是否在体内发生。本研究证实，小鼠淋巴结（murine lymph node, LN）FRC可通过环氧合酶2（cyclooxygenase-2, COX2）依赖且不依赖炎症的方式产生前列腺素E2（prostaglandin E2, PGE2）。研究显示，该COX2/PGE2通路在强弱不同的T细胞应答过程中均处于激活状态，而仅在强T细胞应答中才会激活NO通路。既往研究表明，在体内慢性感染期间，病毒特异性分化簇8（cluster of differentiation 8, CD8）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（CC chemokine ligand, CCL19）启动子调控下表达Cre重组酶的CCL19cre小鼠杂交，鉴定出CCL19+ FRC是产生该COX2依赖性抑制因子的关键来源，提示淋巴组织中表达PGE2的FRC可作为潜在治疗靶点，用于改善慢性感染期间T细胞介导的病原体清除效果。