The B7 family member B7-H3 is broadly expressed in many tissue and tumor types. B7-H3 expression is induced on some immune cells;however, its immunological function remains controversial, because both immunoenhancing ...The B7 family member B7-H3 is broadly expressed in many tissue and tumor types. B7-H3 expression is induced on some immune cells;however, its immunological function remains controversial, because both immunoenhancing and immunoinhibitory effects have been reported in human and mouse systems. We have previously reported the following: 1) murine B7-H3 specifically bound to Triggering receptor expressed on myeloid cells (TREM)-like transcript 2 (TLT-2, TREML2), a member of the TREM family of receptors;and 2) the B7-H3:TLT-2 pathway up-regulated T cell responses. However, the expression and function of human TLT-2 has not yet been clarified. A recent study found no evidence to support the existence of an interacttion between human B7-H3 and TLT-2. In this study, we demonstrated that human B7-H3 binds to TLT-2 and augments T cell responses. Human and mouse B7-H3Ig chimeric proteins cross-interacted with both human and mouse species of TLT-2-transduced cells. Human TLT-2 was expressed on freshly isolated, peripheral blood B cells and monocytes, and subpopulations of CD4+ and CD8+ T cells. Human TLT-2 expression on T cells did not correlate with na?ve or memory phenotypes and was diminished after culture, despite the presence of mitogenic stimuli. Constitutive TLT-2 expression on monocytes was also down-regulated after culture. Human B7-H3 transfectants augment IL-2 production from TLT-2-transduced T cell hybridomas, and IFN-γ production from peripheral blood CD4+ and CD8+ T cells. The enhanced responses were inhibited by the addition of anti-TLT-2 mAbs, suggesting TLT-2-mediated costimulatory effect. Our results demonstrate the existence of a functional interaction between human B7-H3 and TLT-2, and the restricted expression of TLT-2 on T cells and monocytes.展开更多
Geometry optimization and subsequent harmonic vibration calculations of prior synthesized （E）-3-（4-fluorophenyl）-N-[4-（phenyl-amino） quinazoline-7-yl] acrylamide were carried out by DFT/B3LYP method with both 6-...Geometry optimization and subsequent harmonic vibration calculations of prior synthesized （E）-3-（4-fluorophenyl）-N-[4-（phenyl-amino） quinazoline-7-yl] acrylamide were carried out by DFT/B3LYP method with both 6-31G and 6-311G basis sets.The Infrared （IR） spectrum of the title compound was recorded in the field of 400-4000 cm 1 and then assigned.The correlation analyses between the scaled theoretical vibration frequencies and the experimental ones indicate that there exist good linearity relationships since the correlation coefficients R 2 are larger than 0.999.The intramolecular interactions existed in the title molecule were confirmed by the Atoms in molecules （AIM） method,and their influences on the absorption frequency were also investigated.展开更多
Using a newly generated monoclonal antibody （2E6） against human B7-H3, we explored the expression of the molecule on dendritic cells derived from monocytes （Mo-DCs）. Its expression was examined by means of immunos...Using a newly generated monoclonal antibody （2E6） against human B7-H3, we explored the expression of the molecule on dendritic cells derived from monocytes （Mo-DCs）. Its expression was examined by means of immunostaining and flow cytometric （FCM） analysis. The results showed that B7-H3 was expressed in the course of Mo-DC maturation induced with interleukin 4 （IL-4） and granulocyte/macrophage colony-stimulating factor （GM-CSF）. The expression could be detected at all the stages of Mo-DC differentiation, and remained at a quite stable level. Interestingly, B7-H3 was not expressed by T cells and B cells, even these cells were activated respectively by PHA or PWM. A weak expression could be detected on resting monocytes. These data showed that constitutive expression of B7-H3 at a high level was found on imDCs and mDCs derived from monocytes. Due to no expression on T cells and B cells, we speculate that B7-H3 might be another valuable molecule marker for Mo-DCs.展开更多
When the physiopathology of membranous nephropathy was first described,almost 30%of cases were recognized to be secondary to well-known diseases such as autoimmune diseases,tumors or infections.The remaining 70%cases ...When the physiopathology of membranous nephropathy was first described,almost 30%of cases were recognized to be secondary to well-known diseases such as autoimmune diseases,tumors or infections.The remaining 70%cases were called primary membranous nephropathy as the exact mechanism or pathogenic factor involved was unknown.The discovery of the M type phospholipase A2 receptor and thrombospondin type 1 domain containing 7A as causative antigens in these“so called”primary membranous nephropathies provided new insights into the effective causes of a large proportion of these cases.Novel techniques such as laser microdissection and tandem mass spectrometry as well as immunochemistry with antibodies directed against novel proteins allowed the confirmation of new involved antigens.Finally,using confocal microscopy to localize these new antigens and immunoglobulin G and Western blot analysis of serum samples,these new antigens were detected on the glomerular membrane,and the related antibodies were detected in serum samples.The same antigens have been recognized in some cases of secondary membranous disease due to autoimmune diseases,tumors and infections.This has allowed examination of the relationship between antigens in primary membranous nephropathy and their presence in some secondary nephropathies.The aim of this study is to describe the characteristics of the new antigens discovered and their association with other diseases.展开更多
PD-L1 is a member of the B7 protein family,most of whose members so far were identified as dimers in a solution and crystalline state,either complexed or uncomplexed with their ligand(s).The binding of PD-L1 with its ...PD-L1 is a member of the B7 protein family,most of whose members so far were identified as dimers in a solution and crystalline state,either complexed or uncomplexed with their ligand(s).The binding of PD-L1 with its receptor PD-1(CD279)delivers an inhibitory signal regulating the T cell function.Simultaneously with the Garboczi group,we successfully solved another structure of human PD-L1(hPD-L1).Our protein crystallized in the space group of C222_(1) with two hPD-L1 molecules per asymmetric unit.After comparison of reported B7 structures,we have found some intrinsic factors involved in the interaction of these two molecules.Based on these results,we tend to believe this uncomplexed hPD-L1 structure demonstrated its potential dimeric state in solution,althougt it could just be an evolutionary relic,too weak to be detected under present technology,or still a functional unit deserved our attentions.展开更多
Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell dea...Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.展开更多
文摘The B7 family member B7-H3 is broadly expressed in many tissue and tumor types. B7-H3 expression is induced on some immune cells;however, its immunological function remains controversial, because both immunoenhancing and immunoinhibitory effects have been reported in human and mouse systems. We have previously reported the following: 1) murine B7-H3 specifically bound to Triggering receptor expressed on myeloid cells (TREM)-like transcript 2 (TLT-2, TREML2), a member of the TREM family of receptors;and 2) the B7-H3:TLT-2 pathway up-regulated T cell responses. However, the expression and function of human TLT-2 has not yet been clarified. A recent study found no evidence to support the existence of an interacttion between human B7-H3 and TLT-2. In this study, we demonstrated that human B7-H3 binds to TLT-2 and augments T cell responses. Human and mouse B7-H3Ig chimeric proteins cross-interacted with both human and mouse species of TLT-2-transduced cells. Human TLT-2 was expressed on freshly isolated, peripheral blood B cells and monocytes, and subpopulations of CD4+ and CD8+ T cells. Human TLT-2 expression on T cells did not correlate with na?ve or memory phenotypes and was diminished after culture, despite the presence of mitogenic stimuli. Constitutive TLT-2 expression on monocytes was also down-regulated after culture. Human B7-H3 transfectants augment IL-2 production from TLT-2-transduced T cell hybridomas, and IFN-γ production from peripheral blood CD4+ and CD8+ T cells. The enhanced responses were inhibited by the addition of anti-TLT-2 mAbs, suggesting TLT-2-mediated costimulatory effect. Our results demonstrate the existence of a functional interaction between human B7-H3 and TLT-2, and the restricted expression of TLT-2 on T cells and monocytes.
文摘Geometry optimization and subsequent harmonic vibration calculations of prior synthesized （E）-3-（4-fluorophenyl）-N-[4-（phenyl-amino） quinazoline-7-yl] acrylamide were carried out by DFT/B3LYP method with both 6-31G and 6-311G basis sets.The Infrared （IR） spectrum of the title compound was recorded in the field of 400-4000 cm 1 and then assigned.The correlation analyses between the scaled theoretical vibration frequencies and the experimental ones indicate that there exist good linearity relationships since the correlation coefficients R 2 are larger than 0.999.The intramolecular interactions existed in the title molecule were confirmed by the Atoms in molecules （AIM） method,and their influences on the absorption frequency were also investigated.
基金supported by a grant from the National Natural Science Foundation of China(N0.30330540).
文摘Using a newly generated monoclonal antibody （2E6） against human B7-H3, we explored the expression of the molecule on dendritic cells derived from monocytes （Mo-DCs）. Its expression was examined by means of immunostaining and flow cytometric （FCM） analysis. The results showed that B7-H3 was expressed in the course of Mo-DC maturation induced with interleukin 4 （IL-4） and granulocyte/macrophage colony-stimulating factor （GM-CSF）. The expression could be detected at all the stages of Mo-DC differentiation, and remained at a quite stable level. Interestingly, B7-H3 was not expressed by T cells and B cells, even these cells were activated respectively by PHA or PWM. A weak expression could be detected on resting monocytes. These data showed that constitutive expression of B7-H3 at a high level was found on imDCs and mDCs derived from monocytes. Due to no expression on T cells and B cells, we speculate that B7-H3 might be another valuable molecule marker for Mo-DCs.
文摘When the physiopathology of membranous nephropathy was first described,almost 30%of cases were recognized to be secondary to well-known diseases such as autoimmune diseases,tumors or infections.The remaining 70%cases were called primary membranous nephropathy as the exact mechanism or pathogenic factor involved was unknown.The discovery of the M type phospholipase A2 receptor and thrombospondin type 1 domain containing 7A as causative antigens in these“so called”primary membranous nephropathies provided new insights into the effective causes of a large proportion of these cases.Novel techniques such as laser microdissection and tandem mass spectrometry as well as immunochemistry with antibodies directed against novel proteins allowed the confirmation of new involved antigens.Finally,using confocal microscopy to localize these new antigens and immunoglobulin G and Western blot analysis of serum samples,these new antigens were detected on the glomerular membrane,and the related antibodies were detected in serum samples.The same antigens have been recognized in some cases of secondary membranous disease due to autoimmune diseases,tumors and infections.This has allowed examination of the relationship between antigens in primary membranous nephropathy and their presence in some secondary nephropathies.The aim of this study is to describe the characteristics of the new antigens discovered and their association with other diseases.
基金This work was supported by a grant from Ministry of Science and Technology(MOST)of China for the basic research program 973,Grant No.2006CB504204a grant from National Natural Science Foundation(NSFC)of China,Grant No.30671903+3 种基金a grant from Chinese Academy of Sciences(CAS)Knowledge Innovation Project,Grant No.KSCX2-SW-227G.F.G.is a distinguished young investigator of the NSFC(Grant No.30525010)Y.C.is a Ph.D.student supported by Science Innovation Project,Graduate University of Chinese Academy of Sciences(GUCAS),No.0729031EE1The China-Japan Joint Laboratory of Molecular Immunology and Molecular Microbiology is partlially supported by Japan MEXT(Ministry of Education,Culture,Sports,Science and Technology).
文摘PD-L1 is a member of the B7 protein family,most of whose members so far were identified as dimers in a solution and crystalline state,either complexed or uncomplexed with their ligand(s).The binding of PD-L1 with its receptor PD-1(CD279)delivers an inhibitory signal regulating the T cell function.Simultaneously with the Garboczi group,we successfully solved another structure of human PD-L1(hPD-L1).Our protein crystallized in the space group of C222_(1) with two hPD-L1 molecules per asymmetric unit.After comparison of reported B7 structures,we have found some intrinsic factors involved in the interaction of these two molecules.Based on these results,we tend to believe this uncomplexed hPD-L1 structure demonstrated its potential dimeric state in solution,althougt it could just be an evolutionary relic,too weak to be detected under present technology,or still a functional unit deserved our attentions.
基金supported by the National Key Research and Development Program of China(No.2021YFC2700903)the National Natural Science Foundation of China(Nos.81672791 and 81872300)+2 种基金the Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China(No.LR18C060002)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMY22H160006)the ZJU-QILU Joint Research Institute and Qilu Group.
文摘Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.
