Researchers from Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), found that the epigenetic regulator Uhrf1(Ubiquitin-like, containing PHD and RING finger domains) regulates iNKT (invariant Nature Killer T) cell survival and differentiation. Their study was published online in Cell Reports on Mar. 31th.
iNKT cells which are considered as a bridging system between innate and acquired immunity are a unique subset of immune cells with the ability to participate in various diseases such as cancer, autoimmune disease and infection. The function of iNKT cells is acquired during development, making it crucial to understand the regulation of key developmental processes. Although some factors have been reported to function in iNKT cell development, how self-expansion and memory-acquisition are coordinately and dynamically regulated during stage 1 cell transition is poorly understood.
Under the supervision of Prof. LIU Xiaolong at SIBCB, CUI Yu, CHEN Xufeng and colleagues identified that Uhrf1 was significantly upregulated in stage 1 iNKT cells. Targeted disruption of Uhrf1 resulted in stage 1-specific transition defects as observed by not only increased apoptosis, but also aberrant effector differentiation, which eventually led to the impaired generation of iNKT cells in Uhrf1-deficient mice. Notably, Uhrf1 deficiency resulted in attenuated activation of Akt-mTOR signaling in stage 1 iNKT cells and overexpression of active Akt rescued iNKT cell developmental defects.
These findings shed light on the molecular basis for the regulation of stage 1 cell self-expansion and differentiation and provides new understanding for iNKT cell development.
The work entitled “Uhrf1controls iNKT cell survival and differentiation through the Akt-mTOR axis” was technically supported by Dr. XU Chenqi from SIBCB and Dr. BAI Li from University of Science and Technology of China. The current study was supported by grants from 973 program, National Natural Science Foundation of China, and Shanghai Municipality.
CONTACT:
LIU XiaoLong. Ph.D. Professor
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Biochemistry and Cell Biology Building, Rm 815
320 Yueyang Road, Shanghai 200031, China
Tel: 86-21-54921176 Fax: 86-21-54921178
Email: liux@sibs.ac.cn
Link: http://www.sciencedirect.com/science/article/pii/S2211124716302571
Uhrf1 is required for iNKT cell survival and differentiation. The development of iNKT cells undergoes four distinct stages: stage 0, stage 1, stage 2 and stage 3. During the transition from stage 1 to stage 2, iNKT cells undergo several rounds of cell division and acquire a memory/effector phenotype. Acquisition of NK cell lineage markers occurs during stage 2 to stage 3. Uhrf1 showed highest expression in stage 1 iNKT cells, medium expression in stage 2 cells and low expression in stage 0 and stage 3 cells. The high expression of Uhrf1 mediates the activation of Akt-mTOR (mechanistic target of rapamycin) signaling which promotes cell survival and differentiation.
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