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

Yuechen Luo,Zhina Sun,Ting Xue,Song Chen,Fang Liao,Chunxiao Zhao,Fei Yang,Juan Yu,Wenwen Li,Zhongchao Han,Xiaoming Feng,Ling Han,Qing Niu,Yun Zeng,Guogang Xu,Chunming Fang,Tao Cheng,Gang Yu

doi:10.1038/cddis.2016.487

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.

Highlights

Dendritic cells (DCs) are specialized sentinels that induce adaptive immune responses according to environmental stimuli.[1,2] Under steady-state conditions, DCs contribute to immunological tolerance against self-antigens.[3]
We found that the mTORC2 substrate Akt (Ser473),[18] p38MAPK and NF-κB activation were barely altered, and Erk and JNK activation were slightly increased, whereas S6K and PPAR-γ activation were significantly increased in tuberous sclerosis complex 1 (Tsc1)-deificent DCs compared with that in WT cells (Figures 4a and b)
We demonstrated for the first time that Tsc1deficient DCs resulted in the development of lymphoproliferative disorder, disturbed serum immune globulin and limited weight gain in mice, which indicates the role of Tsc[1] in DCs in preserving immune tolerance

Summary

Introduction

Dendritic cells (DCs) are specialized sentinels that induce adaptive immune responses according to environmental stimuli.[1,2] Under steady-state conditions, DCs contribute to immunological tolerance against self-antigens.[3]. Pan et al.[14] reported that Tsc[1] increased IRF4/CIITA/MHC II expression in bone marrow (BM)-derived DCs to enhance OT-II T-cell priming without affecting DC development in response to GM-CSF. Sathaliyawala et al.[9] identified that Tsc[1] loss did not affect DC terminal differentiation or maintenance These results collectively support an important but complex role of Tsc[1] in DC development. Tsc1-deficient DCs showed a defective ability to induce antigen-specific responses in vitro and in vivo as a result of severely reduced number of DCs and hesitated to drive Th2 and Th17 immune response in asthma model. Our data define Tsc[1] as a critical regulator in mature DCs to ensure T-cell homeostasis and immune response

Methods

Results

Conclusion