目的通过阻断小鼠体内T细胞免疫球蛋白黏蛋白分子-3(Tim3)/Galectin9通路,研究Tim3/Galectin9通路在结核菌感染中的调控作用。方法利用Tim3和Galectin9功能性单抗阻断Tim3/Galectin9通路,1.0×10~6CFUH37Rv经腹腔注射感染C57BL/6雌...目的通过阻断小鼠体内T细胞免疫球蛋白黏蛋白分子-3(Tim3)/Galectin9通路,研究Tim3/Galectin9通路在结核菌感染中的调控作用。方法利用Tim3和Galectin9功能性单抗阻断Tim3/Galectin9通路,1.0×10~6CFUH37Rv经腹腔注射感染C57BL/6雌性小鼠,感染4周后观察肺部大体情况和肺组织病理改变;流式细胞术检测小鼠外周血中Th1细胞干扰素-γ(IFN-γ)等细胞因子的表达情况;采用平板计数法计算脾脏和肺脏组织荷菌数CFUs。结果小鼠感染后,经Tim3、Galectin9功能性单抗阻断Tim3/Galectin9通路的小鼠肺部肉芽肿病变明显减轻,脾脏和肺脏的荷菌量均较Ig G control对照组低,流式细胞术结果显示CD4^+T细胞的IFN-γ表达量相比Ig Gcontrol感染对照组增多,差异有统计学意义(P<0.05)。结论结核分枝杆菌感染中,通过功能性单抗阻断Tim3/Galectin9通路可缓解结核病理状态,有效提高机体免疫水平,抑制结核的发生发展。展开更多
Immune effector cells,including cytotoxic T lymphocytes(CTLs)play essential roles in eliminating cancer cells.However,their functionality is often compromised,even when they infiltrate the tumor microenvironment(TME)o...Immune effector cells,including cytotoxic T lymphocytes(CTLs)play essential roles in eliminating cancer cells.However,their functionality is often compromised,even when they infiltrate the tumor microenvironment(TME)or are transferred to cancer patients adoptively.In this study,we focused on galectin 9(G9),an inhibitory ligand that we observed to be predominately positioned on the plasma membrane and readily interacts with CD8+CTL in the TME of nasopharyngeal carcinoma(NPC).We discovered that cell-cell contact between activated effector CTLs and target tumor cells(TarTC)with G9 overexpression led to cellular death defects.Despite the formation of CTL–TarTC conjugates,there is no impact on the cell number nor viability of CTL,and the release of cytolytic content and associated activity were not completely abrogated.Instead,this interaction promoted autophagy and restricted necrosis in the TarTC.Furthermore,reducing G9 expression in tumor cells enhanced the suppressive effect on tumor growth upon adoptive transfer of activated effector CTL.Additionally,inhibiting autophagy effectively controlled tumor growth in cases of G9 overexpression.Therefore,we highlight the contribution of G9 in facilitating the resistance of NPC to CTL-mediated killing by inducing a selection-cell death state in tumor cells,characterized by increased autophagy and decreased necrosis.展开更多
Objective:Adequate extravillous trophoblast(EVT)invasion plays a crucial role in the establishment of successful pregnancy.Insufficient trophoblast migration and invasion can result in defective placentation,which is ...Objective:Adequate extravillous trophoblast(EVT)invasion plays a crucial role in the establishment of successful pregnancy.Insufficient trophoblast migration and invasion can result in defective placentation,which is associated with a number of clinical pathological conditions of pregnancy including spontaneous abortion and preeclampsia.Galectin-9(Gal-9)has a wide variety of regulatory functions in innate and adaptive immunity during infection,tumor growth,and organ transplantation.Methods:We utilized immortalized human first-trimester EVT cells(HTR8/SVneo)for our functional study.We examined the effects of Gal-9 on viability,proliferation,and invasion of HTR8/SVneo cells,as well as on matrix metalloproteinase-2(MMP-2)production in HTR8/SVneo cells.Furthermore,we observed the effects of different MAPK-signaling pathway inhibitors on the stimulatory functions of Gal-9 on HTR8/SVneo cells’invasion.Results:We verified the secretion of Gal-9 by trophoblasts and detected a correlation between low levels of Gal-9 and spontaneous abortion.Gal-9 promoted the invasion of HTR8/SVneo cells through its interaction with Tim-3,not CD44,and subsequently increased MMP-2 production.Blockade of p38 signaling pathway inhibited Gal-9 activities in HTR8/SVneo cells.Conclusion:Gal-9 promotes human trophoblast cell invasion through MMP-2 and p38 signaling pathway in a Tim-3-dependent manner.展开更多
文摘目的通过阻断小鼠体内T细胞免疫球蛋白黏蛋白分子-3(Tim3)/Galectin9通路,研究Tim3/Galectin9通路在结核菌感染中的调控作用。方法利用Tim3和Galectin9功能性单抗阻断Tim3/Galectin9通路,1.0×10~6CFUH37Rv经腹腔注射感染C57BL/6雌性小鼠,感染4周后观察肺部大体情况和肺组织病理改变;流式细胞术检测小鼠外周血中Th1细胞干扰素-γ(IFN-γ)等细胞因子的表达情况;采用平板计数法计算脾脏和肺脏组织荷菌数CFUs。结果小鼠感染后,经Tim3、Galectin9功能性单抗阻断Tim3/Galectin9通路的小鼠肺部肉芽肿病变明显减轻,脾脏和肺脏的荷菌量均较Ig G control对照组低,流式细胞术结果显示CD4^+T细胞的IFN-γ表达量相比Ig Gcontrol感染对照组增多,差异有统计学意义(P<0.05)。结论结核分枝杆菌感染中,通过功能性单抗阻断Tim3/Galectin9通路可缓解结核病理状态,有效提高机体免疫水平,抑制结核的发生发展。
基金supported by Health and Medical Research Fund(HMRF 06172156)and“Laboratory for Synthetic Chemistry and Chemical Biology”under the Health@InnoHK Program launched by Innovation and Technology Commission,The Government of Hong Kong Special Administrative Region of the People’s Republic of ChinaTheme Based Research Scheme(TBRS:T12-703/22-R and T12-703/23-N).
文摘Immune effector cells,including cytotoxic T lymphocytes(CTLs)play essential roles in eliminating cancer cells.However,their functionality is often compromised,even when they infiltrate the tumor microenvironment(TME)or are transferred to cancer patients adoptively.In this study,we focused on galectin 9(G9),an inhibitory ligand that we observed to be predominately positioned on the plasma membrane and readily interacts with CD8+CTL in the TME of nasopharyngeal carcinoma(NPC).We discovered that cell-cell contact between activated effector CTLs and target tumor cells(TarTC)with G9 overexpression led to cellular death defects.Despite the formation of CTL–TarTC conjugates,there is no impact on the cell number nor viability of CTL,and the release of cytolytic content and associated activity were not completely abrogated.Instead,this interaction promoted autophagy and restricted necrosis in the TarTC.Furthermore,reducing G9 expression in tumor cells enhanced the suppressive effect on tumor growth upon adoptive transfer of activated effector CTL.Additionally,inhibiting autophagy effectively controlled tumor growth in cases of G9 overexpression.Therefore,we highlight the contribution of G9 in facilitating the resistance of NPC to CTL-mediated killing by inducing a selection-cell death state in tumor cells,characterized by increased autophagy and decreased necrosis.
基金This work was supported by the National Basic Research Program of China(2015CB9433002017YFC1001400)the National Nature Science Foundation of China(81630036,91542116,31570920,31700799)+2 种基金the Program of Shanghai Academic/Technology Research Leader(17XD1400900)Innovation‑oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation(No.CX2017‑0X)the Shanghai Sailing Program(17YF1411600).
文摘Objective:Adequate extravillous trophoblast(EVT)invasion plays a crucial role in the establishment of successful pregnancy.Insufficient trophoblast migration and invasion can result in defective placentation,which is associated with a number of clinical pathological conditions of pregnancy including spontaneous abortion and preeclampsia.Galectin-9(Gal-9)has a wide variety of regulatory functions in innate and adaptive immunity during infection,tumor growth,and organ transplantation.Methods:We utilized immortalized human first-trimester EVT cells(HTR8/SVneo)for our functional study.We examined the effects of Gal-9 on viability,proliferation,and invasion of HTR8/SVneo cells,as well as on matrix metalloproteinase-2(MMP-2)production in HTR8/SVneo cells.Furthermore,we observed the effects of different MAPK-signaling pathway inhibitors on the stimulatory functions of Gal-9 on HTR8/SVneo cells’invasion.Results:We verified the secretion of Gal-9 by trophoblasts and detected a correlation between low levels of Gal-9 and spontaneous abortion.Gal-9 promoted the invasion of HTR8/SVneo cells through its interaction with Tim-3,not CD44,and subsequently increased MMP-2 production.Blockade of p38 signaling pathway inhibited Gal-9 activities in HTR8/SVneo cells.Conclusion:Gal-9 promotes human trophoblast cell invasion through MMP-2 and p38 signaling pathway in a Tim-3-dependent manner.
