Superantigen-Induced Steroid Resistance Depends on Activation of Phospholipase C beta 2

The glucocorticoid receptor is present in a TCR-associated complex, which includes the Src family tyrosine kinase Lck. Glucocorticoids rapidly dissociate this complex, resulting in the inhibition of canonical Lck-phospholipase C (PLC) gamma-dependent TCR signaling. The relative importance of this nongenomic role for the glucocorticoid receptor compared with its direct transcriptional effects is not known. Superantigens induce a state of steroid resistance in activated T cells. It was reported that, in addition to canonical Lck-PLC gamma signaling, superantigens can activate a noncanonical G protein-PLC beta-dependent signaling pathway. In this study, we show that staphylococcal enterotoxin B activates a Gaq and PLC beta 2-dependent pathway in human T cells. We find that this pathway bypasses the need for canonical Lck-PLC gamma signaling in T cell activation and renders superantigen-stimulated T cells insensitive to glucocorticoids in vitro. We show that the PLCb inhibitor U-73122 sensitizes staphylococcal enterotoxin B-treated mice to dexamethasone in vivo. In conclusion, we find that effects of glucocorticoids on TCR-induced T cell proliferation are mainly nongenomic and can be bypassed by the activation of an Lck-independent signaling pathway.