Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response

Abstract

Dendritic cells (DCs) are pivotal to the induction of adaptive T-cell immune responses. Recent evidence highlights a critical role of tuberous sclerosis complex 1 (Tsc1), a primarily upstream negative regulator of mammalian target of rapamycin (mTOR), in DC development, but whether and how Tsc1 directly regulate mature DC function in vivo remains elusive. Here we show that selective disruption of Tsc1 in DCs results in a lymphoproliferative disorder with the spontaneous activation of T cells. Tsc1 deficiency results in the activation of mTORC1-PPARγ pathway, which leads to the upregulation of neuropilin-1 (Nrp1) expression on DCs to stimulate naive T-cell proliferation. However, Tsc1-deficient DCs have defects in the ability to induce antigen-specific T-cell responses in vitro and in vivo owing to impaired survival during antigen transportation and presentation. Indeed, Tsc1 promotes DC survival through restraining independent mTORC1 and ROS-Bim pathways. Our study identifies Tsc1 as a crucial signaling checkpoint in DCs essential for preserving T-cell homeostasis and response.

Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss

“…Additionally, antioxidant therapy has been attempted with some success in models of noise-induced hearing loss and ARHL (13,53). Recently, ROS levels were reported to be affected by changes in mTORC1 signaling, indicating a link between redox balance and mTORC1 signaling (54)(55)(56). In the present study, levels of 3-NT and 4-HNE, which are markers of ROS, were increased in 1-month-old Tsc1-cKO cochleae, indicating high levels of oxidative stress.…”

Abnormal mTORC1 signaling leads to retinal pigment epithelium degeneration

“…Loss of TSC1 or TSC2 in mouse embryonic fibroblasts leads to endoplasmic reticulum (ER) stress 30. TSC1 prevents dendritic cells from undergoing apoptosis via repressing mTORC1 and reactive oxygen species (ROS) pathways independently 31. ROS generation and ER stress have been associated with RPE degeneration 32.…”

Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy

“…According to a recent study, NRP1 expression on DC may be regulated by the tuberous sclerosis complex I (TSCI); DC specific deletion of TSCI activates the mTOR/PPARγ pathway and upregulates NRP1 expression. This results in hyperproliferation and aberrant activation of naïve T cells in absence of antigen, indicating a requirement for NRP1 in maintaining naïve T cell quiescence under steady state conditions ( 79 ). NRP1 is also expressed on pDCs in the peripheral blood, bone marrow, and cord blood ( 50 , 80 , 81 ).…”