Abstract
Fibroblastic reticular cells (FRCs) in the T cell zone of lymph nodes (LNs) are pivotal for T cell survival, mobility, and peripheral tolerance. Here, we demonstrate that during homeostasis, FRCs also suppress T cell activation via producing high level of prostaglandin E2 (PGE2) due to their thousands-fold higher cyclooxygenase-2 (COX-2) expression than immune cells. This hyperactive COX-2/PGE2-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 Cox-2 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/PGE2 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.
Highlights
Secondary lymphoid organs, such as lymph nodes (LNs), are pivotal for host immunity where a complex network of non-hematopoietic stromal cells organizes immune cells into distinct compartments[1,2,3]
Recent studies demonstrated that Fibroblastic reticular cells (FRCs) of the skin draining lymph nodes (SLNs) play an important role in maintaining peripheral T cell tolerance via presenting peripheral tissue–restricted antigens (PTAs) and elevating nitric oxide (NO) production[11, 12, 14, 15, 35, 36]
Upon T cell activation, NO level in FRC-T cell co-culture reached 1 μM by hours and μM by 48 hours (Fig. S1b), similar to the previous report[13]. These results suggest that the iNOS/NO-pathway was inactive in FRCs during homeostasis or within 24 hours of T cell activation
Summary
Secondary lymphoid organs, such as lymph nodes (LNs), are pivotal for host immunity where a complex network of non-hematopoietic stromal cells organizes immune cells into distinct compartments[1,2,3]. Tumor immunology studies showed that the COX-2/PGE2 pathway is exploited by tumors and myeloid derived suppressor cells (MDSCs) within the tumor microenvironment (TME) as a mechanism of immune evasion and a high expression level of Cox-2, associated with high level of PGE2 production, in these cells is correlated positively with their capacity of T cell suppression[23, 33, 34]. It is yet unknown whether PGE2 directly participates in the maintenance of T cell tolerance during homeostasis. FRCs of human lymphoid tissues share similar hyperactivated COX-2/PEG2 pathway, suggesting a general intrinsic mechanism of FRCs in modulating T cell activation threshold during homeostasis via producing PGE2
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