Leukocyte immunoglobulin(Ig)-like receptors(LILRs),also known as CD85 and immunoglobulin-like transcripts(ILTs),play pivotal roles in regulating immune responses.These receptors define an immune checkpoint that immune...Leukocyte immunoglobulin(Ig)-like receptors(LILRs),also known as CD85 and immunoglobulin-like transcripts(ILTs),play pivotal roles in regulating immune responses.These receptors define an immune checkpoint that immune therapy can target.Through cis or trans interactions with human leukocyte antigen(HLA)-G,the two most abundantly expressed inhibitory LILRs,LILRB1,and LILRB2(LILRB1/2,also known as CD85j/d and ILT2/4),are involved in immunotolerance in pregnancy and transplantation,autoimmune diseases,and immune evasion by tumors.Although the discrete domains of LILRB1/2 are clear,the assembly mode of the four extracellular Ig-like domains(D1,D2,D3,and D4)remains unknown.Previous data indicate that D1D2 is responsible for binding to HLA class I(HLA-I),but the roles of D3D4 are still unclear.Here,we determined the crystal structure of the four Ig-like domain LILRB2 and four-domain LILRB1 in complex with HLA-G1.The angles between adjacent domains and the staggered assembly of the four domains suggest limited flexibility and limited plasticity of the receptors during ligand binding.The complex structure of four domain LILRB1 and HLA-G1 supports the model that D1D2 is responsible for HLA-I binding,while D3D4 acts as a scaffold.Accordingly,cis and trans binding models for HLA-I binding to LILRB1/2 are proposed.The geometries of LILRB1/2 in complex with dimeric and monomeric HLA-G1 suggest the accessibility of the dimeric receptor,which in turn,transduces more inhibitory signals.The assembly of LILRB1/2 and its binding to HLA-G1 could aid in the design of immune regulators and benefit immune interference.展开更多
目的探究不同HIV-1感染者单核细胞亚群中人免疫球蛋白样受体亚家族B成员2(leukocyte immunoglobulin-like receptor subfamily B member 2,LILRB2)与免疫表面相关分子的共表达,分析LILRB2与HIV-1感染免疫重建不良者的相关性。方法选取2...目的探究不同HIV-1感染者单核细胞亚群中人免疫球蛋白样受体亚家族B成员2(leukocyte immunoglobulin-like receptor subfamily B member 2,LILRB2)与免疫表面相关分子的共表达,分析LILRB2与HIV-1感染免疫重建不良者的相关性。方法选取2021年1月—2022年9月,在北京佑安医院感染中心就诊的男男性行为人群(men who have sex with men,MSM)慢性HIV-1感染者为研究对象,将其分为健康对照组(healthy controls,HCs组,n=22)、慢性HIV-1感染且未接受抗病毒治疗组(treatment-naïve patients,TNs组,n=22)、免疫重建良好组(immune responders,IRs组,n=22)和免疫重建不良组(immune non-responders,INRs组,n=22)。流式细胞术检测各组经典型(CD14^(++)CD16-)、中间型(CD14^(++)CD16^(+))、非经典型(CD14^(+)CD16^(++))单核细胞亚群中LILRB2的表达比例,及其与免疫分子CD80、CD86、CD163、人类白细胞DR抗原(HLA-DR)和PD-L1的共表达情况,组间比较采用Kruskal-Wallis检验,然后采用Dunn多重比较进行统计分析。结果INRs组CD14^(+)CD16^(++)单核细胞亚群LILRB2的表达水平显著高于IRs组(P<0.05)、TNs组(P<0.05)和HCs组(P<0.001)。TNs组CD14^(+)CD16^(++)单核细胞LILRB2和CD80的共表达水平显著高于HCs组(P<0.001)、IRs组(P<0.01)和INRs组(P<0.001)。INRs组CD14^(+)CD16^(++)单核细胞亚群LILRB2和CD86的共表达水平显著高于HCs组(P=0.001)、TNs组(P<0.05)和IRs组(P<0.05)。各组CD14^(++)CD16^(+)单核细胞LILRB2和CD163的共表达差异最为显著,其中INRs组显著低于IRs组(P<0.01)和HCs组(P<0.01)。在CD14^(+)CD16^(++)单核细胞中,INRs组和TNs组的HLA-DR和LILRB2共表达情况相近,均显著高于HCs组(P<0.01,P<0.05)。结论LILRB2与HIV-1感染者的单核细胞异常活化有关,其在单核亚群中的表达变化与免疫重建不良的发生存在潜在关联。展开更多
基金supported by the Strategic Priority Research Program of CAS(grant no.XDA12020358)the National Basic Research Program(973)of China(grant no.2015CB910503)+2 种基金the National Natural Science Foundation of China(NSFC,grant nos 31502078 and 31390432)supported by the Youth Innovation Promotion Association CAS(grant no.2018119)supported by the Young Elite Scientist Sponsorship Program by CAST(2016QNRC001)。
文摘Leukocyte immunoglobulin(Ig)-like receptors(LILRs),also known as CD85 and immunoglobulin-like transcripts(ILTs),play pivotal roles in regulating immune responses.These receptors define an immune checkpoint that immune therapy can target.Through cis or trans interactions with human leukocyte antigen(HLA)-G,the two most abundantly expressed inhibitory LILRs,LILRB1,and LILRB2(LILRB1/2,also known as CD85j/d and ILT2/4),are involved in immunotolerance in pregnancy and transplantation,autoimmune diseases,and immune evasion by tumors.Although the discrete domains of LILRB1/2 are clear,the assembly mode of the four extracellular Ig-like domains(D1,D2,D3,and D4)remains unknown.Previous data indicate that D1D2 is responsible for binding to HLA class I(HLA-I),but the roles of D3D4 are still unclear.Here,we determined the crystal structure of the four Ig-like domain LILRB2 and four-domain LILRB1 in complex with HLA-G1.The angles between adjacent domains and the staggered assembly of the four domains suggest limited flexibility and limited plasticity of the receptors during ligand binding.The complex structure of four domain LILRB1 and HLA-G1 supports the model that D1D2 is responsible for HLA-I binding,while D3D4 acts as a scaffold.Accordingly,cis and trans binding models for HLA-I binding to LILRB1/2 are proposed.The geometries of LILRB1/2 in complex with dimeric and monomeric HLA-G1 suggest the accessibility of the dimeric receptor,which in turn,transduces more inhibitory signals.The assembly of LILRB1/2 and its binding to HLA-G1 could aid in the design of immune regulators and benefit immune interference.
文摘目的探究不同HIV-1感染者单核细胞亚群中人免疫球蛋白样受体亚家族B成员2(leukocyte immunoglobulin-like receptor subfamily B member 2,LILRB2)与免疫表面相关分子的共表达,分析LILRB2与HIV-1感染免疫重建不良者的相关性。方法选取2021年1月—2022年9月,在北京佑安医院感染中心就诊的男男性行为人群(men who have sex with men,MSM)慢性HIV-1感染者为研究对象,将其分为健康对照组(healthy controls,HCs组,n=22)、慢性HIV-1感染且未接受抗病毒治疗组(treatment-naïve patients,TNs组,n=22)、免疫重建良好组(immune responders,IRs组,n=22)和免疫重建不良组(immune non-responders,INRs组,n=22)。流式细胞术检测各组经典型(CD14^(++)CD16-)、中间型(CD14^(++)CD16^(+))、非经典型(CD14^(+)CD16^(++))单核细胞亚群中LILRB2的表达比例,及其与免疫分子CD80、CD86、CD163、人类白细胞DR抗原(HLA-DR)和PD-L1的共表达情况,组间比较采用Kruskal-Wallis检验,然后采用Dunn多重比较进行统计分析。结果INRs组CD14^(+)CD16^(++)单核细胞亚群LILRB2的表达水平显著高于IRs组(P<0.05)、TNs组(P<0.05)和HCs组(P<0.001)。TNs组CD14^(+)CD16^(++)单核细胞LILRB2和CD80的共表达水平显著高于HCs组(P<0.001)、IRs组(P<0.01)和INRs组(P<0.001)。INRs组CD14^(+)CD16^(++)单核细胞亚群LILRB2和CD86的共表达水平显著高于HCs组(P=0.001)、TNs组(P<0.05)和IRs组(P<0.05)。各组CD14^(++)CD16^(+)单核细胞LILRB2和CD163的共表达差异最为显著,其中INRs组显著低于IRs组(P<0.01)和HCs组(P<0.01)。在CD14^(+)CD16^(++)单核细胞中,INRs组和TNs组的HLA-DR和LILRB2共表达情况相近,均显著高于HCs组(P<0.01,P<0.05)。结论LILRB2与HIV-1感染者的单核细胞异常活化有关,其在单核亚群中的表达变化与免疫重建不良的发生存在潜在关联。
