Efficient immune responses rely on the proper differentiation of CD8^(+)T cells into effector and memory cells.Here,we show a critical requirement of N^6-Methyladenosine(m^(6)A)methyltransferase Mettl3 during CD8^(+)T...Efficient immune responses rely on the proper differentiation of CD8^(+)T cells into effector and memory cells.Here,we show a critical requirement of N^6-Methyladenosine(m^(6)A)methyltransferase Mettl3 during CD8^(+)T cell responses upon acute viral infection.Conditional deletion of Mettl3 in CD8^(+)T cells impairs effector expansion and terminal differentiation in an m^(6)A-dependent manner,subsequently affecting memory formation and the secondary response of CD8^(+)T cells.Our combined RNA-seq and m^(6)AmiCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and transcriptional regulators.Remarkably,Mettl3 binds to the Tbx21 transcript and stabilizes it,promoting effector differentiation of CD8^(+)T cells.Moreover,ectopic expression of T-bet partially restores the defects in CD8^(+)T cell differentiation in the absence of Mettl3.Thus,our study highlights the role of Mettl3 in regulating multiple target genes in an m^(6)A-dependent manner and underscores the importance of m^(6)A modification during CD8^(+)T cell response.展开更多
Invariant natural killer T(iNKT)cells are highly conserved innate-like T lymphocytes that originate from CD4^(+)CD8^(+)double-positive(DP)thymocytes.Here,we report that serine/arginine splicing factor 1(SRSF1)intrinsi...Invariant natural killer T(iNKT)cells are highly conserved innate-like T lymphocytes that originate from CD4^(+)CD8^(+)double-positive(DP)thymocytes.Here,we report that serine/arginine splicing factor 1(SRSF1)intrinsically regulates iNKT cell development by directly targeting Myb and balancing the abundance of short and long isoforms.Conditional ablation of SRSF1 in DP cells led to a substantially diminished iNKT cell pool due to defects in proliferation,survival,and TCRαrearrangement.The transition from stage 0 to stage 1 of iNKT cells was substantially blocked,and the iNKT2 subset was notably diminished in SRSF1-deficient mice.SRSF1 deficiency resulted in aberrant expression of a series of regulators that are tightly correlated with iNKT cell development and iNKT2 differentiation,including Myb,PLZF,Gata3,ICOS,and CD5.In particular,we found that SRSF1 directly binds and regulates pre-mRNA alternative splicing of Myb and that the expression of the short isoform of Myb is substantially reduced in SRSF1-deficient DP and iNKT cells.Strikingly,ectopic expression of the Myb short isoform partially rectified the defects caused by ablation of SRSF1.Furthermore,we confirmed that the SRSF1-deficient mice exhibited resistance to acute liver injury uponα-GalCer and Con A induction.Our findings thus uncovered a previously unknown role of SRSF1 as an essential post-transcriptional regulator in iNKT cell development and functional differentiation,providing new clinical insights into iNKT-correlated disease.展开更多
Dear Editor,The diversity and composition of gut microbiota play critical roles for maintaining the homeostasis of host commensal bacteria which are correlated with mammalian health(Ding and Schloss,2014).Disorder of ...Dear Editor,The diversity and composition of gut microbiota play critical roles for maintaining the homeostasis of host commensal bacteria which are correlated with mammalian health(Ding and Schloss,2014).Disorder of microbial community is implicated in the pathogenesis of several human diseases,such as autoimmune disease,allergy,diabetes,obesity,and inflammatory bowel disease(IBD),which is clearly demonstrated to relate to gut dysbiosis in patients and mouse models(Saleh and Elson,2011).展开更多
基金the National Natural Science Foundation of China(32130039,31970831,81970541,31960151,and 31630038)the National Key Research and Development Program of China(2017YFA0104401)+3 种基金the Pinduoduo-China Agricultural University Research Fund(PC2023B01011)Frontiers Science Center for Molecular Design Breeding(MOE),Chinese Universities Scientific Fund(2022TC030 and 2021TC087)the Project for Extramural Scientists of State Key Laboratory of Agrobiotechnology from China Agricultural University(2021SKLAB6-3 and 2021SKLAB6-4)the Collaborative Innovation Center of Chinese Ministry of Education(2020-39)。
文摘Efficient immune responses rely on the proper differentiation of CD8^(+)T cells into effector and memory cells.Here,we show a critical requirement of N^6-Methyladenosine(m^(6)A)methyltransferase Mettl3 during CD8^(+)T cell responses upon acute viral infection.Conditional deletion of Mettl3 in CD8^(+)T cells impairs effector expansion and terminal differentiation in an m^(6)A-dependent manner,subsequently affecting memory formation and the secondary response of CD8^(+)T cells.Our combined RNA-seq and m^(6)AmiCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and transcriptional regulators.Remarkably,Mettl3 binds to the Tbx21 transcript and stabilizes it,promoting effector differentiation of CD8^(+)T cells.Moreover,ectopic expression of T-bet partially restores the defects in CD8^(+)T cell differentiation in the absence of Mettl3.Thus,our study highlights the role of Mettl3 in regulating multiple target genes in an m^(6)A-dependent manner and underscores the importance of m^(6)A modification during CD8^(+)T cell response.
基金This work was supported in part by grants from the National Key Research and Development Program of China(2017YFA0104401)the National Natural Scientific Foundation of China(32130039,31970831,and 31630038)the Project for Extramural Scientists of State Key Laboratory of Agrobiotechnology from China Agricultural University(2021SKLAB6-3,2021SKLAB6-4,2019SKLAB6-6,and 2019SKLAB6-7).
文摘Invariant natural killer T(iNKT)cells are highly conserved innate-like T lymphocytes that originate from CD4^(+)CD8^(+)double-positive(DP)thymocytes.Here,we report that serine/arginine splicing factor 1(SRSF1)intrinsically regulates iNKT cell development by directly targeting Myb and balancing the abundance of short and long isoforms.Conditional ablation of SRSF1 in DP cells led to a substantially diminished iNKT cell pool due to defects in proliferation,survival,and TCRαrearrangement.The transition from stage 0 to stage 1 of iNKT cells was substantially blocked,and the iNKT2 subset was notably diminished in SRSF1-deficient mice.SRSF1 deficiency resulted in aberrant expression of a series of regulators that are tightly correlated with iNKT cell development and iNKT2 differentiation,including Myb,PLZF,Gata3,ICOS,and CD5.In particular,we found that SRSF1 directly binds and regulates pre-mRNA alternative splicing of Myb and that the expression of the short isoform of Myb is substantially reduced in SRSF1-deficient DP and iNKT cells.Strikingly,ectopic expression of the Myb short isoform partially rectified the defects caused by ablation of SRSF1.Furthermore,we confirmed that the SRSF1-deficient mice exhibited resistance to acute liver injury uponα-GalCer and Con A induction.Our findings thus uncovered a previously unknown role of SRSF1 as an essential post-transcriptional regulator in iNKT cell development and functional differentiation,providing new clinical insights into iNKT-correlated disease.
基金This work is supported by National Key R&D Program of China(2017YFA0104401)to S.Y.National Natural Science Foundation of China(Grant Nos.31571522,31970831,31630038 and 31422037)to S.Y.the Project for Extramural Scientists of State Key Laboratory of Agrobiotechnology from China Agricultural University,China(2019SKLAB6-6).
文摘Dear Editor,The diversity and composition of gut microbiota play critical roles for maintaining the homeostasis of host commensal bacteria which are correlated with mammalian health(Ding and Schloss,2014).Disorder of microbial community is implicated in the pathogenesis of several human diseases,such as autoimmune disease,allergy,diabetes,obesity,and inflammatory bowel disease(IBD),which is clearly demonstrated to relate to gut dysbiosis in patients and mouse models(Saleh and Elson,2011).
