Fibroblastic reticular cells of the secondary lymphoid organ suppress T cell activation via COX2 mediated PGE2 secretion.

Abstract

Abstract Accumulating evidence demonstrates that fibroblastic reticular cells (FRCs) in the T cell zone of the secondary lymphoid organs (SLO), characterized as CD45− gp38+CD31− cells, play an important role in maintaining T cell tolerance via presenting peripheral tissue–restricted antigens (PTAs) and/or interferon-induced nitric oxide during productive immunity. Here, using FRCs harvested from naïve mice, we revealed that FRCs also inhibit T cell activation via a soluble factor, independent of the aforementioned mechanisms. Specifically, FRCs suppressed CD3/CD28-ligation mediated or antigen induced antigen-specific T cell activation. This FRC-imposed suppression was demonstrated as (1) reduced Zap-70 phosphorylation and Calcium-flux within 30 minutes of TCR-ligation, (2) inhibited upregulation of surface CD69 and CD44 expression and downregulation of CD62L 6–14 hours post-activation, and (3) suppressed T cell effector cytokine production and proliferation. Further studies demonstrated that our observed inhibition of T cell activation by FRC is at least partially contributed by cyclooxygenase-2 (COX-2) mediated production of prostaglandin E2 (PGE2) because COX-2 inhibitor partially reversed FRC mediated inhibition. ELISA results confirmed high production level of PGE2 by FRC (~ 10 – 50ng/ml), at which level T cell activation is greatly suppressed. Taken together, our study illustrated another previously unrecognized mechanism of FRCs in maintaining T cell tolerance, which underscores the crucial role of FRCs in peripheral tolerance and immune regulation. The potential molecular mechanism by which the COX2-PGE2 pathway is activated in FRCs under physiological condition will be discussed.