mTOR Activation Underlies Enhanced B Cell Proliferation and Autoimmunity in PrkcdG510S/G510S Mice

Abstract

Autosomal recessive PRKCD deficiency has previously been associated with the development of systemic lupus erythematosus in human patients, but the mechanisms underlying autoimmunity remain poorly understood. We introduced the Prkcd G510S mutation that we previously associated to a Mendelian cause of systemic lupus erythematosus in the mouse genome, using CRISPR-Cas9 gene editing. PrkcdG510S/G510S mice recapitulated the human phenotype and had reduced lifespan. We demonstrate that this phenotype is linked to a B cell–autonomous role of Prkcd. A detailed analysis of B cell activation in PrkcdG510S/G510S mice shows an upregulation of the PI3K/mTOR pathway after the engagement of the BCR in these cells, leading to lymphoproliferation. Treatment of mice with rapamycin, an mTORC1 inhibitor, significantly improves autoimmune symptoms, demonstrating in vivo the deleterious effect of mTOR pathway activation in PrkcdG510S/G510S mice. Additional defects in PrkcdG510S/G510S mice include a decrease in peripheral mature NK cells that might contribute to the known susceptibility to viral infections of patients with PRKCD mutations.

Discovery of a novel ROS-based signature for predicting prognosis and immunosuppressive tumor microenvironment in lung adenocarcinoma

“…PKCδ, encoded by PRKCD , is a cytoplasmic enzyme within the diacylglycerol-responsive and calcium-independent serine/threonine PKC family and acts as a regulatory molecule for apoptosis, being responsive to a spectrum of cellular stress factors, including ultraviolet light exposure, DNA-damaging agents, ROS, growth-promoting signals, and cytokines 64 . It influences cellular behaviors like survival, division, movement, and programmed cell death 65 . Additionally, this kinase has a widespread presence and fulfills various roles within the cellular components of innate and adaptive immunity 65 .…”

“…It influences cellular behaviors like survival, division, movement, and programmed cell death 65 . Additionally, this kinase has a widespread presence and fulfills various roles within the cellular components of innate and adaptive immunity 65 . PKC-δ is known to govern the migration of neutrophils and their capacity for an oxidative burst 66 , 67 , and it contributes to the functional capacities of macrophages 68 , proliferation and cytokine synthesis in T cells, and B cell receptor signaling pathways 69 .…”

Signaling Pathways Leading to mTOR Activation Downstream Cytokine Receptors in Lymphocytes in Health and Disease

“…The notion that mTORC1 activity is essential for lymphocyte activation and functions stems from earlier studies that discovered the immunosuppressive activity of rapamycin [ 9 ]. mTORC1 inhibitors have thus been used in clinics, notably in the context of lymphoproliferative diseases [ 10 , 11 , 12 ] or organ transplantation [ 13 , 14 ]. Therefore, the essential role of mTOR for immune cell development and function is now widely recognized, especially in lymphocytes [ 15 ].…”