Bacterial Superantigens Bypass Lck-Dependent T Cell Receptor Signaling by Activating a Gα11-Dependent, PLC-β-Mediated Pathway

Abstract

The paradigm to explain antigen-dependent T cell receptor (TCR) signaling is based on the activation of the CD4 or CD8 coreceptor-associated kinase Lck. It is widely assumed that this paradigm is also applicable to signaling by bacterial superantigens. However, these bacterial toxins can activate human T cells lacking Lck, suggesting the existence of an additional pathway of TCR signaling. Here we showed that this alternative pathway operates in the absence of Lck-dependent tyrosine-phosphorylation events and was initiated by the TCR-dependent activation of raft-enriched heterotrimeric Galpha11 proteins. This event, in turn, activated a phospholipase C-beta and protein kinase C-mediated cascade that turned on the mitogen-activated protein kinases ERK-1 and ERK-2, triggered Ca(2+) influx, and translocated the transcription factors NF-AT and NF-kappaB to the nucleus, ultimately inducing the production of interleukin-2 in Lck-deficient T cells. The triggering of this alternative pathway by superantigens suggests that these toxins use a G protein-coupled receptor as a coreceptor on T cells.

Unchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis

“…The system therefore allows for comparing high-affinity and low-affinity human T cell responses, which is otherwise not possible because of the low frequency of human T cells to nominal peptides. Superantigen-mediated T cell stimulation employs regular T cell recognition synapse formation; however, recent studies have also shown that superantigens can bypass the Lck dependence of the TCR signaling pathways (45), suggesting that superantigen stimulation is an imperfect, although currently the best, experimental system to study human naive T cell responses. In particular, TSST may be the best superantigenic model because of the unique structure of the MHC-TSST-TCR complex (46).…”

Superantigen-Induced Steroid Resistance Depends on Activation of Phospholipase Cβ2

“…This is why we examined the effect of glucocorticoids on SEB-mediated T cell activation. It was reported that SEB activates PLCb-dependent signaling in a Jurkat T cell line, in addition to Lck-PLCg signaling (8). This is why we determined whether this PLCb-mediated bypass of Lck-PLCg signaling is responsible for SEB-induced steroid insensitivity that was described in human PBMCs (7).…”

“…Superantigens were reported to cause steroid resistance in T cells (7). More importantly, it was shown that superantigens can activate a noncanonical G protein-PLCb signaling pathway in addition to canonical Lck-PLCg signaling (8). If steroid-mediated inhibition of T cell proliferation depends mainly on nongenomic inhibition of canonical T cell signaling, this predicts that superantigen-mediated glucocorticoid resistance depends on PLCb signaling.…”

“…To further address this question, we used the superantigen SEB. SEB not only activates canonical Lck-PLCg signaling, it was also reported to activate a noncanonical G protein-PLCb-dependent signaling pathway (8). If the effects of glucocorticoids depend on inhibition of Lck, this predicts that superantigen-induced T cell proliferation is only partially responsive to glucocorticoids.…”

“…It was suggested that Ga11 acts upstream of PLCb activation in Jurkat T cells (8). We first used quantitative RT-PCR to examine the expression of both Gaq and Ga11 in Jurkat cells and primary human CD4 + T lymphocytes using testis as a positive control for Ga11 and monocytes as a positive control for Gaq (Fig.…”