Background:Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma(MM)progression.Simultaneously,previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upo...Background:Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma(MM)progression.Simultaneously,previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with commonγ-chain family cytokines in vitro and during homeostatic proliferation.The aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets upregulating PD-1 and TIM-3 checkpoint molecules.Methods:The expression of CD25,CD122,CD127 commonγ-chain cytokine receptors,phosphorylated signal transducer and activator of transcription-5(pSTAT5)and eomesodermin(EOMES)was comparatively assessed with flow cytometry in PD-1-and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM patients.Results:Substantial proportions of PD-1-and TIM-3-positive T lymphocytes expressed commonγ-chain cytokine receptors and pSTAT5.Frequencies of cytokine receptor expressing cells were significantly higher within TIM-3+T cells compared to PD-1+TIM-3−subsets.Considerable proportions of both PD-1-/TIM-3-negative and positive CD8+T cells express EOMES,while only moderate frequencies of CD4+PD-1+/TIM-3+T cells up-regulate this transcription factor.Besides,the surface presence of CD25 and intranuclear expression of EOMES in CD4+T cells were mutually exclusive regardless of PD-1 and TIM-3 expression.The stimulation with commonγ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+and TIM-3+T cell subsets in vitro.Conclusions:Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine stimulation.Differences in commonγ-chain cytokine receptor expression between PD-1+and TIM-3+T cells may reflect functional dissimilarity of these cell subsets.Checkpoint blockade appears to alleviate lymphopenia-induced proliferation of PD-1+T cells but may raise the possibility of immune-mediated adverse events.展开更多
Eomesodermin(Eomes)is a critical factor in the development of natural killer(NK)cells,but its precise role in temporal and spatial coordination during this process remains unclear.Our study revealed that Eomes plays d...Eomesodermin(Eomes)is a critical factor in the development of natural killer(NK)cells,but its precise role in temporal and spatial coordination during this process remains unclear.Our study revealed that Eomes plays distinct roles during the early and late stages of NK cell development.Specifically,the early deletion of Eomes via the CD122-Cre transgene resulted in significant blockade at the progenitor stage due to the downregulation of KLF2,another important transcription factor.ChIP-seq revealed direct binding of Eomes to the conserved noncoding sequence(CNS)of Klf2.Utilizing the CHimeric IMmune Editing(CHIME)technique,we found that deletion of the CNS region of Klf2 via CRISPRi led to a reduction in the NK cell population and developmental arrest.Moreover,constitutive activation of this specific CNS region through CRISPRa significantly reversed the severe defects in NK cell development caused by Eomes deficiency.Conversely,Ncr1-Cre-mediated terminal deletion of Eomes expedited the transition of NK cell subsets from the CD27+CD11b+phenotype to the CD27−CD11b+phenotype.Late-stage deficiency of Eomes led to a significant increase in T-bet expression,which subsequently increased the expression of the transcription factor Zeb2.Genetic deletion of one allele of Tbx21,encoding T-bet,effectively reversed the aberrant differentiation of Eomes-deficient NK cells.In summary,we utilized two innovative genetic models to elucidate the intricate mechanisms underlying Eomes-mediated NK cell commitment and differentiation.展开更多
为了保持电光调制器(EOM)输入光偏振方向始终与其内部可传播模式偏振方向一致,使EOM获得良好的调制效果,提出了一种基于比例-积分-微分(PID)算法的EOM自适应偏振控制方法,理论分析并实验验证了该方法的可行性。实验结果表明,基于该方法...为了保持电光调制器(EOM)输入光偏振方向始终与其内部可传播模式偏振方向一致,使EOM获得良好的调制效果,提出了一种基于比例-积分-微分(PID)算法的EOM自适应偏振控制方法,理论分析并实验验证了该方法的可行性。实验结果表明,基于该方法设计的控制系统不仅能实时监测EOM输出光功率,而且能保持其输出光功率最大;与激光器和EOM输入端直接用保偏光纤连接时相比,PID偏振控制下EOM输出平均功率提高了3.08 d B,PD输出电压标准差由0.121 4降至1.237 5×10-4,稳定控制状态下偏振态矫正时间在ms量级。展开更多
文摘Background:Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma(MM)progression.Simultaneously,previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with commonγ-chain family cytokines in vitro and during homeostatic proliferation.The aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets upregulating PD-1 and TIM-3 checkpoint molecules.Methods:The expression of CD25,CD122,CD127 commonγ-chain cytokine receptors,phosphorylated signal transducer and activator of transcription-5(pSTAT5)and eomesodermin(EOMES)was comparatively assessed with flow cytometry in PD-1-and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM patients.Results:Substantial proportions of PD-1-and TIM-3-positive T lymphocytes expressed commonγ-chain cytokine receptors and pSTAT5.Frequencies of cytokine receptor expressing cells were significantly higher within TIM-3+T cells compared to PD-1+TIM-3−subsets.Considerable proportions of both PD-1-/TIM-3-negative and positive CD8+T cells express EOMES,while only moderate frequencies of CD4+PD-1+/TIM-3+T cells up-regulate this transcription factor.Besides,the surface presence of CD25 and intranuclear expression of EOMES in CD4+T cells were mutually exclusive regardless of PD-1 and TIM-3 expression.The stimulation with commonγ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+and TIM-3+T cell subsets in vitro.Conclusions:Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine stimulation.Differences in commonγ-chain cytokine receptor expression between PD-1+and TIM-3+T cells may reflect functional dissimilarity of these cell subsets.Checkpoint blockade appears to alleviate lymphopenia-induced proliferation of PD-1+T cells but may raise the possibility of immune-mediated adverse events.
基金supported by the Natural Science Foundation of China(32330034,31830027,31821003,82271754 and 82071737)the National Key Research&Developmental Program of China(2022YFF0710602)+1 种基金the Excellent Research and Innovation Team in Anhui Province’s Universities(2023AH010085)the China Postdoctoral Science Foundation(2020M670296 and 2021T140372).
文摘Eomesodermin(Eomes)is a critical factor in the development of natural killer(NK)cells,but its precise role in temporal and spatial coordination during this process remains unclear.Our study revealed that Eomes plays distinct roles during the early and late stages of NK cell development.Specifically,the early deletion of Eomes via the CD122-Cre transgene resulted in significant blockade at the progenitor stage due to the downregulation of KLF2,another important transcription factor.ChIP-seq revealed direct binding of Eomes to the conserved noncoding sequence(CNS)of Klf2.Utilizing the CHimeric IMmune Editing(CHIME)technique,we found that deletion of the CNS region of Klf2 via CRISPRi led to a reduction in the NK cell population and developmental arrest.Moreover,constitutive activation of this specific CNS region through CRISPRa significantly reversed the severe defects in NK cell development caused by Eomes deficiency.Conversely,Ncr1-Cre-mediated terminal deletion of Eomes expedited the transition of NK cell subsets from the CD27+CD11b+phenotype to the CD27−CD11b+phenotype.Late-stage deficiency of Eomes led to a significant increase in T-bet expression,which subsequently increased the expression of the transcription factor Zeb2.Genetic deletion of one allele of Tbx21,encoding T-bet,effectively reversed the aberrant differentiation of Eomes-deficient NK cells.In summary,we utilized two innovative genetic models to elucidate the intricate mechanisms underlying Eomes-mediated NK cell commitment and differentiation.
文摘为了保持电光调制器(EOM)输入光偏振方向始终与其内部可传播模式偏振方向一致,使EOM获得良好的调制效果,提出了一种基于比例-积分-微分(PID)算法的EOM自适应偏振控制方法,理论分析并实验验证了该方法的可行性。实验结果表明,基于该方法设计的控制系统不仅能实时监测EOM输出光功率,而且能保持其输出光功率最大;与激光器和EOM输入端直接用保偏光纤连接时相比,PID偏振控制下EOM输出平均功率提高了3.08 d B,PD输出电压标准差由0.121 4降至1.237 5×10-4,稳定控制状态下偏振态矫正时间在ms量级。
