CD3ε of T cell antigen receptor complex (TCR/CD3) plays an important role in the resembling of the complex and activation signaling through its conservative immunoreceptor tyrosine-based activation motif (ITAM) in th...CD3ε of T cell antigen receptor complex (TCR/CD3) plays an important role in the resembling of the complex and activation signaling through its conservative immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic tail. Previous study showed that a chimera molecule, consisting of the extracellular-transmembrane domain of human CD8α fused to the cytoplasmic domain of CD3ε, induced apoptosis of T lymphocytes, indicating that apoptotic signals were transduced through the CD3ε- ITAM. To elineate involvement of the two tyrosines in apoptotic signaling pathway, cDNAs with mutations at Y170F, Y181F and Y170F/Y181F in CD8-ε-ITAM were made by point mutation and PCR, and then cloned into pcDNA3 eukaryotic expression vectors. Stable expression cell lines were established after transfection of the expression vectors into CD8+- Jurkat T lymphocytes. Stimulation of these cell lines with anti-CD8 monoclonal antibody showed that only the cells with expression of wild type chimera CD8-ε died by apoptosis, but not those cells with expressions of mutated CD8-ε chimera, indicating that the two tyrosines in CD3ε-ITAM were required for the apoptotic signal transduction in T lymphocytes.展开更多
IgA Fc受体(FcαRI,CD89)属于免疫受体家族成员,主要表达于单核-巨噬细胞、中性粒细胞、嗜酸性粒细胞和树突状细胞等免疫效应细胞表面。FcαRI能特异的与血清型和分泌型IgA结合,并通过γ链介导一系列免疫反应,包括抗体依赖细胞介导的细...IgA Fc受体(FcαRI,CD89)属于免疫受体家族成员,主要表达于单核-巨噬细胞、中性粒细胞、嗜酸性粒细胞和树突状细胞等免疫效应细胞表面。FcαRI能特异的与血清型和分泌型IgA结合,并通过γ链介导一系列免疫反应,包括抗体依赖细胞介导的细胞毒性作用(ADCC)、补体依赖的细胞毒性(CDC)及细胞吞噬作用等。FcαRI是一种双功能受体,在不同的生理条件下可以介导免疫系统的活化和抑制反应。FcαRI在机体免疫防御和在维持系统免疫平衡方面扮演着重要的角色,有望成为治疗人类疾病的新靶点。本文对FcαRI的结构、功能及其应用等研究现状进行综述。展开更多
Among many factors known to alter the outcomes of T cell receptor(TCR)-induced proximal signaling,the role of human germline variants in dictating the individuality of the anti-tumor CD8 T cell response has remained c...Among many factors known to alter the outcomes of T cell receptor(TCR)-induced proximal signaling,the role of human germline variants in dictating the individuality of the anti-tumor CD8 T cell response has remained challenging to address.Here,we describe a convenient strategy for molecular and functional characterization of phosphotyrosine-altering non-synonymous single nucleotide variations(pTyr-SNVs)that directly impact TCR-induced proximal phosphotyrosine motif-based signaling pathways.We devise an experimental co-cultivation set-up comprising a C57BL/6 mouse-derived metastatic melanoma cell line engineered to constitutively present ovalbumin(OVA)antigens and retrovirally engineered syngeneic major histocompatibility complex(MHC)Class I restricted OVA TCR-transgenic CD8 T cells(OT-I).Using the synthetic version of pTyr-SNV rs1178800678-G/T-encoding integrin alpha 4(ITGA4)p.S1027I variant as a prototype,we show that under identical TCR stimulation conditions,genetically determined membrane-proximal immunoreceptor tyrosin activation motif(ITAM)results in increased tyrosine phosphorylation of 70 kDa zeta-chain-associated protein(ZAP70)and the levels of cytotoxic effector molecule granzyme B(GZMB),which in turn result in enhanced cytotoxic activity against metastatic melanoma cell line.This strategy paves the way for rapid molecular and functional characterization of anti-tumor immune response-linked germline pTyr-SNVs so as to improve our understanding of the genetic basis of individual-to-individual differences in anti-tumor CD8 T cell response.展开更多
Modulation by balancing activating and inhibitory receptors constitutes an important mechanism for regulating immune responses.Cells that are activated following ligation of receptors bearing immunoreceptor tyrosine-b...Modulation by balancing activating and inhibitory receptors constitutes an important mechanism for regulating immune responses.Cells that are activated following ligation of receptors bearing immunoreceptor tyrosine-based activation motifs (ITAMs) can be negatively regulated by other receptors bearing immuno- receptor tyrosine-based inhibition motifs (ITIMs).Human mast cells (MCs) are the major effector cells of type Ⅰ hypersensitivity and important participants in a number of disease processes.Antigen-mediated aggregation of IgE bound to its high-affinity receptor on MCs initiates a complex series of biochemical events leading to MC activation.With great detailed description and analysis of several inhibitory receptors on human MCs,a central paradigm of negative regulation of human MC activation by these receptors has emerged.Cellular & Molecular Immunology.2004;1(6):408-415.展开更多
Inhibitory leukocyte immunoglobulin-like receptors(LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs(ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, ...Inhibitory leukocyte immunoglobulin-like receptors(LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs(ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-1), protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-2), or Src homology 2 domain containing inositol phosphatase(SHIP) to negatively regulate immune cell activation. These receptors are known to play important regulatory roles in immune and neuronal functions. Recent studies demonstrated that several of these receptors are expressed by cancer cells. Importantly, they may directly regulate development, drug resistance, and relapse of cancer, and the activity of cancer stem cells. Although counterintuitive, these findings are consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system. This review focuses on the ligands, expression pattern, signaling, and function of LILRB family in the context of cancer development. Because inhibition of the signaling of certain LILRBs directly blocks cancer growth and stimulates immunity that may suppress tumorigenesis, but does not disturb normal development, LILRB signaling pathways may represent ideal targets for treating hematological malignancies and perhaps other tumors.展开更多
文摘CD3ε of T cell antigen receptor complex (TCR/CD3) plays an important role in the resembling of the complex and activation signaling through its conservative immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic tail. Previous study showed that a chimera molecule, consisting of the extracellular-transmembrane domain of human CD8α fused to the cytoplasmic domain of CD3ε, induced apoptosis of T lymphocytes, indicating that apoptotic signals were transduced through the CD3ε- ITAM. To elineate involvement of the two tyrosines in apoptotic signaling pathway, cDNAs with mutations at Y170F, Y181F and Y170F/Y181F in CD8-ε-ITAM were made by point mutation and PCR, and then cloned into pcDNA3 eukaryotic expression vectors. Stable expression cell lines were established after transfection of the expression vectors into CD8+- Jurkat T lymphocytes. Stimulation of these cell lines with anti-CD8 monoclonal antibody showed that only the cells with expression of wild type chimera CD8-ε died by apoptosis, but not those cells with expressions of mutated CD8-ε chimera, indicating that the two tyrosines in CD3ε-ITAM were required for the apoptotic signal transduction in T lymphocytes.
文摘Among many factors known to alter the outcomes of T cell receptor(TCR)-induced proximal signaling,the role of human germline variants in dictating the individuality of the anti-tumor CD8 T cell response has remained challenging to address.Here,we describe a convenient strategy for molecular and functional characterization of phosphotyrosine-altering non-synonymous single nucleotide variations(pTyr-SNVs)that directly impact TCR-induced proximal phosphotyrosine motif-based signaling pathways.We devise an experimental co-cultivation set-up comprising a C57BL/6 mouse-derived metastatic melanoma cell line engineered to constitutively present ovalbumin(OVA)antigens and retrovirally engineered syngeneic major histocompatibility complex(MHC)Class I restricted OVA TCR-transgenic CD8 T cells(OT-I).Using the synthetic version of pTyr-SNV rs1178800678-G/T-encoding integrin alpha 4(ITGA4)p.S1027I variant as a prototype,we show that under identical TCR stimulation conditions,genetically determined membrane-proximal immunoreceptor tyrosin activation motif(ITAM)results in increased tyrosine phosphorylation of 70 kDa zeta-chain-associated protein(ZAP70)and the levels of cytotoxic effector molecule granzyme B(GZMB),which in turn result in enhanced cytotoxic activity against metastatic melanoma cell line.This strategy paves the way for rapid molecular and functional characterization of anti-tumor immune response-linked germline pTyr-SNVs so as to improve our understanding of the genetic basis of individual-to-individual differences in anti-tumor CD8 T cell response.
文摘Modulation by balancing activating and inhibitory receptors constitutes an important mechanism for regulating immune responses.Cells that are activated following ligation of receptors bearing immunoreceptor tyrosine-based activation motifs (ITAMs) can be negatively regulated by other receptors bearing immuno- receptor tyrosine-based inhibition motifs (ITIMs).Human mast cells (MCs) are the major effector cells of type Ⅰ hypersensitivity and important participants in a number of disease processes.Antigen-mediated aggregation of IgE bound to its high-affinity receptor on MCs initiates a complex series of biochemical events leading to MC activation.With great detailed description and analysis of several inhibitory receptors on human MCs,a central paradigm of negative regulation of human MC activation by these receptors has emerged.Cellular & Molecular Immunology.2004;1(6):408-415.
基金supported b y the Na tional In stitu te o f Health(1R01CA172268)the Leukemia&Lymphoma Society(1024-14+7 种基金TRP-6024-14)the Robert A.Welch Foundation(I-1834)the Cancer Prevention and Research Institute of Texas(RP140402 and DP150056)the Innovation Program of Shanghai Municipal Education Commission(13G20)the Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learningthe National Natural Science Foundation of China(813706548142200181471524)
文摘Inhibitory leukocyte immunoglobulin-like receptors(LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs(ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-1), protein tyrosine phosphatase, non-receptor type 6(PTPN6, SHP-2), or Src homology 2 domain containing inositol phosphatase(SHIP) to negatively regulate immune cell activation. These receptors are known to play important regulatory roles in immune and neuronal functions. Recent studies demonstrated that several of these receptors are expressed by cancer cells. Importantly, they may directly regulate development, drug resistance, and relapse of cancer, and the activity of cancer stem cells. Although counterintuitive, these findings are consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system. This review focuses on the ligands, expression pattern, signaling, and function of LILRB family in the context of cancer development. Because inhibition of the signaling of certain LILRBs directly blocks cancer growth and stimulates immunity that may suppress tumorigenesis, but does not disturb normal development, LILRB signaling pathways may represent ideal targets for treating hematological malignancies and perhaps other tumors.
