Protein kinase C signaling during T cell activation induces the endoplasmic reticulum stress response

Abstract

T cell receptor (TCR) ligation (signal one) in the presence of co-stimulation (signal two) results in downstream signals that increase protein production enabling naïve T cells to fully activate and gain effector function. Enhanced production of proteins by a cell requires an increase in endoplasmic reticulum (ER) chaperone expression, which is accomplished through activation of a cellular mechanism known as the ER stress response. The ER stress response is initiated during the cascade of events that occur for the activation of many cells; however, this process has not been comprehensively studied for T cell function. In this study, we used primary T cells and mice circulating TCR transgenic CD8(+) T cells to investigate ER chaperone expression in which TCR signaling was initiated in the presence or absence of co-stimulation. In the presence of both signals, in vitro and in vivo analyses demonstrated induction of the ER stress response, as evidenced by elevated expression of GRP78 and other ER chaperones. Unexpectedly, ER chaperones were also increased in T cells exposed only to signal one, a treatment known to cause T cells to enter the 'nonresponsive' states of anergy and tolerance. Treatment of T cells with an inhibitor to protein kinase C (PKC), a serine/threonine protein kinase found downstream of TCR signaling, indicated PKC is involved in the induction of the ER stress response during the T cell activation process, thus revealing a previously unknown role for this signaling protein in T cells. Collectively, these data suggest that induction of the ER stress response through PKC signaling is an important component for the preparation of a T cell response to antigen.

Wogonin ameliorates lipotoxicity-induced apoptosis of cultured vascular smooth muscle cells via interfering with DAG-PKC pathway

“…Our results show that pre-treatment with wogonin significantly reduces the intracellular DAG levels and attenuates PKC phosphorylation (Figure 7). Because activated PKCs may contribute to altered cellular functions such as regulating signaling function of the ER [54,55] and enhancing ROS production [51] , our data suggest that the DAG/PKC pathway mediates palmitate-induced apoptosis and overgenerated ROS production in VSMCs, and that wogonin ameliorates palmitate-induced ER stress by inhibiting the DAG-PKC pathway.…”

Endoplasmic Reticulum Stress Response Promotes Cytotoxic Phenotype of CD8αβ+ Intraepithelial Lymphocytes in a Mouse Model for Crohn’s Disease-like Ileitis

“…This hypothesis was supported by the finding that Ca 2+ chelators abrogated TCR-mediated Grp78 expression. In contrast, Pino et al (47) argued that the protein kinase C-signaling pathway controls TCR-mediated Grp78 expression and additionally affects IL-2 expression. Consistently, we demonstrated that IL-2 expression and T cell proliferation are controlled by Grp78.…”

“…Two recent reports attempted to identify the signaling pathways triggering Grp78 expression after TCR activation (46,47). Takano et al (46) reported that this process might be regulated by the calcineurin-NFAT pathway.…”

“…Franco et al (45) reported that ER stress is also involved in the induction and plastic differentiation of regulatory peripheral T cells. Recent studies indicated that Grp78 expression in conventional CD4 + or CD8ab + T cells is induced by CD3:TCR activation or mitogenic stimulation (46,47). This was shown to be mediated by protein kinase C, because blocking of protein kinase C resulted in diminished ER stress response and reduced IL-2 synthesis in T cells (47).…”

“…Recent studies indicated that Grp78 expression in conventional CD4 + or CD8ab + T cells is induced by CD3:TCR activation or mitogenic stimulation (46,47). This was shown to be mediated by protein kinase C, because blocking of protein kinase C resulted in diminished ER stress response and reduced IL-2 synthesis in T cells (47). A knock down of Grp78 protein induced apoptosis in a murine T cell line (46).…”