Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell–dendritic cell interactions

Abstract

Interactions between dendritic cells (DCs) and T cells control the decision between activation and tolerance induction. Thromboxane A2 (TXA2) and its receptor TP have been suggested to regulate adaptive immune responses through control of T cell–DC interactions. Here, we show that this control is achieved by selectively reducing expansion of low-avidity CD4+ T cells. During inflammation, weak tetramer-binding TP-deficient CD4+ T cells were preferentially expanded compared with TP-proficient CD4+ T cells. Using intravital imaging of cellular interactions in reactive peripheral lymph nodes (PLNs), we found that TXA2 led to disruption of low- but not high-avidity interactions between DCs and CD4+ T cells. Lack of TP correlated with higher expression of activation markers on stimulated CD4+ T cells and with augmented accumulation of follicular helper T cells (TFH), which correlated with increased low-avidity IgG responses. In sum, our data suggest that tonic suppression of weak CD4+ T cell–DC interactions by TXA2–TP signaling improves the overall quality of adaptive immune responses.