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Here, we demonstrate that during homeostasis, FRCs also suppress T cell activation via producing high level of prostaglandin E<jats:sub>2<\/jats:sub>(PGE<jats:sub>2<\/jats:sub>) due to their thousands-fold higher cyclooxygenase-2 (COX-2) expression than immune cells. This hyperactive COX-2\/PGE<jats:sub>2<\/jats:sub>-induced suppression is evident during antigen-specific and non-antigen-specific activations. It is implicated as suppressed TCR-signaling cascades, reduced alterations in activation markers, and inhibited cytokine production of freshly isolated T cells or T cells co-cultured with FRCs compared with those cultured without FRCs. Different from T cell dysfunction, this FRC-mediated suppression is surmountable by enhancing the strength of stimulation and is reversible by COX-2 inhibitors. Furthermore, T cells in the FRC environment where<jats:italic>Cox-2<\/jats:italic>is genetic inactivated are more sensitive and rapidly activated upon stimulations than those in WT environment. Significantly, FRCs of human lymphoid organs manifest similar COX-2\/PGE<jats:sub>2<\/jats:sub>hyperactivity and T cell suppression. Together, this study identifies a previously unappreciated intrinsic mechanism of FRCs shared between mice and humans for suppressing T cell sensitivity to activation via PGE2, underscoring the importance of FRCs in shaping the suppressive milieu of lymphoid organs during homeostasis.<\/jats:p>","DOI":"10.1038\/s41598-017-03459-5","type":"journal-article","created":{"date-parts":[[2017,6,7]],"date-time":"2017-06-07T09:40:46Z","timestamp":1496828446000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Fibroblastic reticular cells of the lymphoid tissues modulate T cell activation threshold during homeostasis via hyperactive cyclooxygenase-2\/prostaglandin E2 axis"],"prefix":"10.1038","volume":"7","author":[{"given":"Miao","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roni","family":"Bollag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,6,13]]},"reference":[{"key":"3459_CR1","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1038\/ni1513","volume":"8","author":"A Link","year":"2007","unstructured":"Link, A. et al. 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