We recently demonstrated that leukocyte Ig-like receptor 4(LILRB4)expressed by monocytic acute myeloid leukemia(AML)cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain.The cyto...We recently demonstrated that leukocyte Ig-like receptor 4(LILRB4)expressed by monocytic acute myeloid leukemia(AML)cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain.The cytoplasmic domain of LILRB4 contains three immunoreceptor tyrosine-based inhibitory motifs(ITIMs);the tyrosines at positions 360,412,and 442 are phosphorylation sites.Here,we analyzed how the ITIMs of LILRB4 in AML cells mediate its function.Our in vitro and in vivo data show that Y412 and Y442,but not Y360,of LILRB4 are required for T-cell inhibition,and all three ITIMs are needed for leukemia cell infiltration.We constructed chimeric proteins containing the extracellular domain of LILRB4 and the intracellular domain of LILRB1 and vice versa.The intracellular domain of LILRB4,but not that of LILRB1,mediates T-cell suppression and AML cell migration.Our studies thus defined the unique signaling roles of LILRB4 ITIMs in AML cells.展开更多
Fc Receptor-Like 1(FCRL1),a member of the FCRL family,contains two immunoreceptor tyrosinebased activation motifs(ITAMs)in its cytoplasmic domain and plays a critical role in B-cell biology.Its expression begins in pr...Fc Receptor-Like 1(FCRL1),a member of the FCRL family,contains two immunoreceptor tyrosinebased activation motifs(ITAMs)in its cytoplasmic domain and plays a critical role in B-cell biology.Its expression begins in pre-B-cells,dynamically shifts during B-cell development,and contributes to the regulation of human B-cell activation.Notably,FCRL1 is overexpressed in subsets of naive and memory B-cells,as well as in malignant B-cells,including those in diffuse large B-cell lymphoma(DLBCL),an aggressive and often treatment-resistant hematological malignancy.Among FCRL family members,FCRL1 stands out as a promising immunotherapeutic target due to its selective expression in malignant B-cells and its functional role in proliferation.Given the limited efficacy of current therapies for relapsed/refractory DLBCL,targeting FCRL1 could address an unmet clinical need by offering a novel,mechanism-based approach to modulate B-cell signaling and enhance anti-tumor immunity.This mini-review highlights the therapeutic potential of FCRL1-directed strategies,supporting their further exploration in preclinical models and future clinical trials for DLBCL and other B-cell malignancies.展开更多
基金We thank the National Cancer Institute(1R01CA172268)the Cancer Prevention and Research Institute of Texas(RP180435)+3 种基金the Robert A.Welch Foundation(I-1834)China Natural Science Foundation(81872332)Shandong Natural Science Foundation(2018GSF118201)Yantai Science and Technology Development Plan(2018ZHGY070)for generous support.
文摘We recently demonstrated that leukocyte Ig-like receptor 4(LILRB4)expressed by monocytic acute myeloid leukemia(AML)cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain.The cytoplasmic domain of LILRB4 contains three immunoreceptor tyrosine-based inhibitory motifs(ITIMs);the tyrosines at positions 360,412,and 442 are phosphorylation sites.Here,we analyzed how the ITIMs of LILRB4 in AML cells mediate its function.Our in vitro and in vivo data show that Y412 and Y442,but not Y360,of LILRB4 are required for T-cell inhibition,and all three ITIMs are needed for leukemia cell infiltration.We constructed chimeric proteins containing the extracellular domain of LILRB4 and the intracellular domain of LILRB1 and vice versa.The intracellular domain of LILRB4,but not that of LILRB1,mediates T-cell suppression and AML cell migration.Our studies thus defined the unique signaling roles of LILRB4 ITIMs in AML cells.
基金supported by funding from the Veterans Administration(I01 BX006101-01)supported in part by funding from the Veterans Administration(IO1 BX001262)the recipient of RCS Award(IK6 BX005964)from the Department of Veterans Administration.
文摘Fc Receptor-Like 1(FCRL1),a member of the FCRL family,contains two immunoreceptor tyrosinebased activation motifs(ITAMs)in its cytoplasmic domain and plays a critical role in B-cell biology.Its expression begins in pre-B-cells,dynamically shifts during B-cell development,and contributes to the regulation of human B-cell activation.Notably,FCRL1 is overexpressed in subsets of naive and memory B-cells,as well as in malignant B-cells,including those in diffuse large B-cell lymphoma(DLBCL),an aggressive and often treatment-resistant hematological malignancy.Among FCRL family members,FCRL1 stands out as a promising immunotherapeutic target due to its selective expression in malignant B-cells and its functional role in proliferation.Given the limited efficacy of current therapies for relapsed/refractory DLBCL,targeting FCRL1 could address an unmet clinical need by offering a novel,mechanism-based approach to modulate B-cell signaling and enhance anti-tumor immunity.This mini-review highlights the therapeutic potential of FCRL1-directed strategies,supporting their further exploration in preclinical models and future clinical trials for DLBCL and other B-cell malignancies.
文摘目的:初步探讨慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)患者外周血共抑制分子T细胞免疫球蛋白和ITIM结构域(T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain,TIGIT)和程序性细胞死亡受体1(programmed cell death protein 1,PD-1)在Tfh细胞上的表达变化特点及临床意义。方法:采用流式细胞术检测50例CLL患者、36例非CLL的慢性B淋巴细胞增殖疾病患者和30例健康者外周血Tfh细胞百分比和Tfh细胞上PD-1和TIGIT的水平,比较3组受试者的差异。分析CLL患者TIGIT+PD-1+Tfh细胞百分比与IPI评分分层的关系,以及与免疫球蛋白的相关性。结果:(1)与对照组比较,初诊CLL患者Tfh、PD-1+Tfh、TIGIT+Tfh、TIGIT+PD-1+Tfh、TIGIT+PD-1-Tfh和TIGIT-PD-1+Tfh细胞百分比明显增高,差异有统计学意义(P<0.05)。(2)TIGIT+PD-1+Tfh细胞在CLL-IPI预后分层低危组、中危组、高危组、极高危组比较分析结果,组间和组内两两比较差异均有统计学意义(P<0.05),随着预后分层增加TIGIT+PD-1+Tfh细胞水平逐渐增加。(3)受试者工作特征曲线结果显示,TIGIT+PD-1+Tfh细胞在CLL患者和非CLL患者的鉴别诊断中具有一定的诊断价值(P<0.05)。(4)Logistic回归分析显示,TIGIT+PD-1+Tfh细胞百分比是CLL发病的独立危险因素(P<0.05)。(5)CLL患者外周血中TIGIT+PD-1+Tfh与IgA、IgM、IgG均呈负相关(P<0.05)。结论:初诊CLL患者外周血TIGIT+PD-1+Tfh细胞百分比明显增加,Tfh细胞高表达共抑制分子TIGIT和PD-1参与CLL疾病的发生,并且与疾病的免疫球蛋白水平降低有关。
