CHOP mediates PKC-theta (PKCθ) deficient T cell apoptosis (145.1)

Abstract Endoplasmic reticulum (ER) stress, a signaling pathway, is activated when unfolded proteins accumulate in the ER. Sustained activation of ER stress triggers proapoptotic signals via CCAAT/enhancer-binding protein homologous protein (CHOP) that elicits cell apoptosis. PKCθ deficient T cells have revealed spontaneous and TCR/CD28-induced apoptosis, reduced NF-kB activation, and unresponsiveness to cardiac allografts. However, whether PKCθ deficiency-induced tolerance is associated with CHOP expression remains unknown. Here we show that CHOP expression was increased in the cardiac allografts, spleens, and thymus of PKCθ-/- mice. Increased CHOP expression is associated with increased PKCθ-/- T cell apoptosis (Annex V positive cells) and Bax expression. There were no significant changes of other ER stress proteins, such as calnexin and IRE-1α, and chaperones in PKCθ-/- mice. LC3-I to LC3-II conversion represents an activation of autophagy and can be induced by ER stress; however, there was no increased LC3-I to LC3-II conversion in PKCθ-/- mice. The cardiac allografts were accepted in PKCθ and CD28 double knockout (PKCθ-/-/CD28-/-) mice, and activation of NF-kB by TLR engagement with CpG ODNs inhibited CHOP expression and triggered allograft rejection. Our data suggest that PKCθ deficiency stimulates the CHOP signaling pathway, which mediates T cell apoptosis and is negatively regulated by NF-kB activation.