Thymic natural killer T(NKT)2 cells are a subset of invariant NKT cells with PLZF^(hi)GATA3^(hi)IL-4^(+).The differentiation of NKT2 cells is not fully understood.In the present study,we report an important role of TR...Thymic natural killer T(NKT)2 cells are a subset of invariant NKT cells with PLZF^(hi)GATA3^(hi)IL-4^(+).The differentiation of NKT2 cells is not fully understood.In the present study,we report an important role of TRAF3-interacting protein 3(TRAF3IP3)in the functional maturation and expansion of committed NKT2s in thymic medulla.Mice with T-cell-specific deletion of TRAF3IP3 had decreased thymic NKT2 cells,decreased IL-4-producing peripheral iNKTs,and defects in response toα-galactosylceramide.Positive selection and high PLZF expression in CD24^(+)CD44^(−) and CCR7^(+)CD44^(−) immature iNKTs were not affected.Only CD44^(hi)NK1.1^(−) iNKTs in Traf3ip3^(−/−) mice showed reduced expression of Egr2,PLZF,and IL-17RB,decreased proliferation,and reduced IL-4 production upon stimulation.This Egr2 and IL-4 expression was augmented by MEK1/ERK activation in iNKTs,and TRAF3IP3 at the trans-Golgi network recruited MEK1 and facilitated ERK phosphorylation and nuclear translocation.LT βR-regulated bone marrow-derived nonlymphoid cells in the medullary thymic microenvironment were required for MEK/ERK activation and NKT2 maturation.These data demonstrate an important functional maturation process in NKT2 differentiation that is regulated by MEK/ERK signaling at the trans-Golgi network.展开更多
Clinical cell therapies(CTs)for neurological diseases and cellular damage have been explored for more than 2 decades.According to the United States Food and Drug Administration,there are 2 types of cell categories for...Clinical cell therapies(CTs)for neurological diseases and cellular damage have been explored for more than 2 decades.According to the United States Food and Drug Administration,there are 2 types of cell categories for therapy,namely stem cell-derived CT products and mature/functionally differentiated cell-derived CT products.However,regardless of the type of CT used,the majority of reports of clinical CTs from either small sample sizes based on single-center phase 1 or 2 unblinded trials or retrospective clinical studies showed effects on neurological improvement and the ability to either partially or temporarily thwart the deteriorating cellular processes of the neurodegenerative diseases.There have been only a few prospective,multicenter,randomized,double-blind placebo-control clinical trials of CTs so far in this developing novel area that have shown negative results,and more clinical trials are needed.This will expand our knowledge in exploring the type of cells that yield promising results and restore damaged neurological structure and functions of the central nervous system based on higher level evidence-based medical data.In this review,we briefly introduce the developmental process,current state,and future prospective for clinical neurorestorative CT.展开更多
基金supported by grants from the National Key Research and Development Program of China(2017YFA0104500)the National Natural Science Foundation of China(81471525,31671244,31872734,Q.G.,31872824,H.Z.)+1 种基金the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(81621001)the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences,2018PT31039.
文摘Thymic natural killer T(NKT)2 cells are a subset of invariant NKT cells with PLZF^(hi)GATA3^(hi)IL-4^(+).The differentiation of NKT2 cells is not fully understood.In the present study,we report an important role of TRAF3-interacting protein 3(TRAF3IP3)in the functional maturation and expansion of committed NKT2s in thymic medulla.Mice with T-cell-specific deletion of TRAF3IP3 had decreased thymic NKT2 cells,decreased IL-4-producing peripheral iNKTs,and defects in response toα-galactosylceramide.Positive selection and high PLZF expression in CD24^(+)CD44^(−) and CCR7^(+)CD44^(−) immature iNKTs were not affected.Only CD44^(hi)NK1.1^(−) iNKTs in Traf3ip3^(−/−) mice showed reduced expression of Egr2,PLZF,and IL-17RB,decreased proliferation,and reduced IL-4 production upon stimulation.This Egr2 and IL-4 expression was augmented by MEK1/ERK activation in iNKTs,and TRAF3IP3 at the trans-Golgi network recruited MEK1 and facilitated ERK phosphorylation and nuclear translocation.LT βR-regulated bone marrow-derived nonlymphoid cells in the medullary thymic microenvironment were required for MEK/ERK activation and NKT2 maturation.These data demonstrate an important functional maturation process in NKT2 differentiation that is regulated by MEK/ERK signaling at the trans-Golgi network.
文摘Clinical cell therapies(CTs)for neurological diseases and cellular damage have been explored for more than 2 decades.According to the United States Food and Drug Administration,there are 2 types of cell categories for therapy,namely stem cell-derived CT products and mature/functionally differentiated cell-derived CT products.However,regardless of the type of CT used,the majority of reports of clinical CTs from either small sample sizes based on single-center phase 1 or 2 unblinded trials or retrospective clinical studies showed effects on neurological improvement and the ability to either partially or temporarily thwart the deteriorating cellular processes of the neurodegenerative diseases.There have been only a few prospective,multicenter,randomized,double-blind placebo-control clinical trials of CTs so far in this developing novel area that have shown negative results,and more clinical trials are needed.This will expand our knowledge in exploring the type of cells that yield promising results and restore damaged neurological structure and functions of the central nervous system based on higher level evidence-based medical data.In this review,we briefly introduce the developmental process,current state,and future prospective for clinical neurorestorative CT.
