The spatiotemporal distribution of cytokines orchestrates immune responses in vivo,yet the underlying mechanisms remain to be explored.We showed here that the spatial distribution of interleukin-4(IL4)in invariant nat...The spatiotemporal distribution of cytokines orchestrates immune responses in vivo,yet the underlying mechanisms remain to be explored.We showed here that the spatial distribution of interleukin-4(IL4)in invariant natural killer T(iNKT)cells regulated crosstalk between iNKT cells and dendritic cells(DCs)and controlled iNKT cell-mediated T-helper type 1(Th1)responses.The persistent polarization of IL4 induced by strong lipid antigens,that is,α-galactosylceramide(αGC),caused IL4 accumulation at the immunological synapse(IS),which promoted the activation of the IL4R-STAT6(signal transducer and activator of transcription 6)pathway and production of IL12 in DCs,which enhanced interferon-γ(IFNγ)production in iNKT cells.Conversely,the nonpolarized secretion of IL4 induced by Th2 lipid antigens with a short or unsaturated chain was incapable of enhancing this iNKT cell-DC crosstalk and thus shifted the immune response to a Th2-type response.The nonpolarized secretion of IL4 in response to Th2 lipid antigens was caused by the degradation of Cdc42 in iNKT cells.Moreover,reduced Cdc42 expression was observed in tumorinfiltrating iNKT cells,which impaired IL4 polarization and disturbed iNKT cell-DC crosstalk in tumors.展开更多
目的研究IL-4调控树突状细胞特异性非整合素(dendritic-cell specific ICAM-3 grabbing non-integrin,DC-SIGN)的表达对树突状细胞免疫学功能的影响,以探讨DC-SIGN表达与结核病发生的关系。方法用不同剂量的IL-4(5、10、50、100、200ng/...目的研究IL-4调控树突状细胞特异性非整合素(dendritic-cell specific ICAM-3 grabbing non-integrin,DC-SIGN)的表达对树突状细胞免疫学功能的影响,以探讨DC-SIGN表达与结核病发生的关系。方法用不同剂量的IL-4(5、10、50、100、200ng/ml)调控DCs表面DC-SIGN的表达水平;根据加入IL-4剂量将DCs分为5ng/ml组和50ng/ml组,分别加入100ng/ml的脂多糖(lipopolysaccharide,LPS)、结核杆菌H37Rv菌悬液共培养。应用流式细胞仪检测各组DCs表型(CD11c、DC-SIGN、CD83、CD86、HLA-DR),ELISA法检测细胞培养液中IL-12、IL-10含量,混合淋巴细胞培养法检测各组DCs刺激T淋巴细胞增殖的能力。结果①IL-4能调控DC-SIGN的表达水平,并呈剂量依赖性,当加入IL-4的剂量由5ng/ml增加到50ng/ml时,DC-SIGN的表达水平显著增加(P<0.05)。当IL-4的剂量由50ng/ml增至200ng/ml时,DC-SIGN的表达水平虽仍随IL-4剂量增加而增加,但差异无统计学意义(P>0.05)。②表达不同水平DC-SIGN的DCs成熟度无显著差异(P>0.05)。③表达不同水平DC-SIGN的DCs加入LPS、H37Rv诱导后,培养液中IL-12含量无显著差异(P>0.05),加入LPS诱导后培养液中IL-10含量也无显著差异(P>0.05),但DC-SIGNhigh-DCs加入H37Rv诱导后培养液中IL-10含量明显高于DC-SIGNlow-DCs(P<0.05)。④表达不同水平DC-SIGN的DCs加入LPS诱导后刺激同种异体T淋巴细胞增殖能力差异无统计学意义(P>0.05)。DC-SIGNhigh-DCs加入H37Rv诱导成熟后与DCs加入LPS诱导成熟后刺激同种异体T淋巴细胞增殖的能力相当(P>0.05),但DC-SIGNlow-DCs加入H37Rv诱导后刺激同种异体T淋巴细胞增殖能力明显低于其他3组(P<0.05)。结论DC-SIGNhigh-DCs加入H37Rv诱导后分泌IL-10水平明显高于DC-SIGNlow-DCs,但DC-SIGNlow-DCs加入H37Rv诱导后刺激T淋巴细胞增殖的能力明显降低。DC-SIGN表达过高或过低均不利于机体抗结核免疫应答。展开更多
基金This work was supported by National Key R&D Program of China 2017YFA0505300the National Natural Science Foundation of China 91542203 and 81771671+1 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences XDA12030208the Fundamental Research Funds for the Central Universities.
文摘The spatiotemporal distribution of cytokines orchestrates immune responses in vivo,yet the underlying mechanisms remain to be explored.We showed here that the spatial distribution of interleukin-4(IL4)in invariant natural killer T(iNKT)cells regulated crosstalk between iNKT cells and dendritic cells(DCs)and controlled iNKT cell-mediated T-helper type 1(Th1)responses.The persistent polarization of IL4 induced by strong lipid antigens,that is,α-galactosylceramide(αGC),caused IL4 accumulation at the immunological synapse(IS),which promoted the activation of the IL4R-STAT6(signal transducer and activator of transcription 6)pathway and production of IL12 in DCs,which enhanced interferon-γ(IFNγ)production in iNKT cells.Conversely,the nonpolarized secretion of IL4 induced by Th2 lipid antigens with a short or unsaturated chain was incapable of enhancing this iNKT cell-DC crosstalk and thus shifted the immune response to a Th2-type response.The nonpolarized secretion of IL4 in response to Th2 lipid antigens was caused by the degradation of Cdc42 in iNKT cells.Moreover,reduced Cdc42 expression was observed in tumorinfiltrating iNKT cells,which impaired IL4 polarization and disturbed iNKT cell-DC crosstalk in tumors.
文摘目的研究IL-4调控树突状细胞特异性非整合素(dendritic-cell specific ICAM-3 grabbing non-integrin,DC-SIGN)的表达对树突状细胞免疫学功能的影响,以探讨DC-SIGN表达与结核病发生的关系。方法用不同剂量的IL-4(5、10、50、100、200ng/ml)调控DCs表面DC-SIGN的表达水平;根据加入IL-4剂量将DCs分为5ng/ml组和50ng/ml组,分别加入100ng/ml的脂多糖(lipopolysaccharide,LPS)、结核杆菌H37Rv菌悬液共培养。应用流式细胞仪检测各组DCs表型(CD11c、DC-SIGN、CD83、CD86、HLA-DR),ELISA法检测细胞培养液中IL-12、IL-10含量,混合淋巴细胞培养法检测各组DCs刺激T淋巴细胞增殖的能力。结果①IL-4能调控DC-SIGN的表达水平,并呈剂量依赖性,当加入IL-4的剂量由5ng/ml增加到50ng/ml时,DC-SIGN的表达水平显著增加(P<0.05)。当IL-4的剂量由50ng/ml增至200ng/ml时,DC-SIGN的表达水平虽仍随IL-4剂量增加而增加,但差异无统计学意义(P>0.05)。②表达不同水平DC-SIGN的DCs成熟度无显著差异(P>0.05)。③表达不同水平DC-SIGN的DCs加入LPS、H37Rv诱导后,培养液中IL-12含量无显著差异(P>0.05),加入LPS诱导后培养液中IL-10含量也无显著差异(P>0.05),但DC-SIGNhigh-DCs加入H37Rv诱导后培养液中IL-10含量明显高于DC-SIGNlow-DCs(P<0.05)。④表达不同水平DC-SIGN的DCs加入LPS诱导后刺激同种异体T淋巴细胞增殖能力差异无统计学意义(P>0.05)。DC-SIGNhigh-DCs加入H37Rv诱导成熟后与DCs加入LPS诱导成熟后刺激同种异体T淋巴细胞增殖的能力相当(P>0.05),但DC-SIGNlow-DCs加入H37Rv诱导后刺激同种异体T淋巴细胞增殖能力明显低于其他3组(P<0.05)。结论DC-SIGNhigh-DCs加入H37Rv诱导后分泌IL-10水平明显高于DC-SIGNlow-DCs,但DC-SIGNlow-DCs加入H37Rv诱导后刺激T淋巴细胞增殖的能力明显降低。DC-SIGN表达过高或过低均不利于机体抗结核免疫应答。
