免疫突触形成的生物学特点及其光学成像研究
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摘要
免疫突触(immunological synapse,IS)是抗原提呈细胞与T细胞免疫识别时,多种分子参与、分阶段不断变化的过程,涉及黏附分子、细胞因子、信号传导分子、细胞骨架蛋白等多分子的聚集或离散.其形成不仅促进T细胞和抗原提呈细胞的稳定接触,而且激活T细胞信号传导途径,促进T细胞的活化和增殖.对IS的研究可以从分子水平解释免疫激活、免疫耐受、病原微生物感染与免疫细胞相互作用的机制,为进一步揭示疾病发生的分子机制,寻求疾病防治的靶向分子提供新的思路.近年来,光学成像的发展为可视化研究IS形成与T细胞活化的关系提供了有力帮助,为研究生理病理状态下的免疫应答提供了有力工具.
Immunological synapse(IS) is a specialized and sophisticated supramolecular activation cluster structure that is formed at the interface between T cell and antigen presenting cells. It is a dynamic multistage progress, involving adhesion molecules, cytokines, signaling molecules, cell cytoskeletal proteins and other molecules. IS is not only contribute to the stability of the contact between T cells and APC, but also promotes T-cell activation and proliferation through T cells signaling pathway. Studying of the immunological synapse could explain molecular mechanisms of immune activation, immune tolerance, and the mechanism of interaction between pathogenic microbes and immune cells, which will provide new ideas for further revealing the pathogenic mechanism of disease, and seeking new target molecules for disease control and prevention. Recently, optical imaging provides a powerful help for visualization on the relationship between IS formation and T-cell activation.It provides a powerful tool for studying the immune response under physiological and pathological conditions.
Immunological synapse(IS) is a specialized and sophisticated supramolecular activation cluster structure that is formed at the interface between T cell and antigen presenting cells. It is a dynamic multistage progress, involving adhesion molecules, cytokines, signaling molecules, cell cytoskeletal proteins and other molecules. IS is not only contribute to the stability of the contact between T cells and APC, but also promotes T-cell activation and proliferation through T cells signaling pathway. Studying of the immunological synapse could explain molecular mechanisms of immune activation, immune tolerance, and the mechanism of interaction between pathogenic microbes and immune cells, which will provide new ideas for further revealing the pathogenic mechanism of disease, and seeking new target molecules for disease control and prevention. Recently, optical imaging provides a powerful help for visualization on the relationship between IS formation and T-cell activation.It provides a powerful tool for studying the immune response under physiological and pathological conditions.
引文
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[2]Grakoui A,Bromley S K,Sumen C,et al.The immunological synapse:a molecular machine controlling T cell activation.Science,1999,285(5425):221-227
[3]Lee K H,Holdorf a D,Dustin M L,et al.T cell receptor signaling precedes immunological synapse formation.Science,2002,295(5559):1539-1542
[4]Lee K H,Dinner a R,Tu C,et al.The immunological synapse balances T cell receptor signaling and degradation.Science,2003,302(5648):1218-1222
[5]Lee S J,Hori Y,Groves J T,et al.The synapse assembly model.Trends Immunol,2002,23(10):500-502
[6]Friedman R S,Beemiller P,Sorensen C M,et al.Real-time analysis of T cell receptors in naive cells in vitro and in vivo reveals flexibility in synapse and signaling dynamics.J Exp Med,2010,207(12):2733-2749
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[8]Shakhar G,Lindquist R L,Skokos D,et al.Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo.Nat Immunol,2005,6(7):707-714
[9]Yan J,Liu B,Shi Y,et al.Class II MHC-independent suppressive adhesion of dendritic cells by regulatory T cells in vivo.J Exp Med,2017,214(2):319-326
[10]Chen J,Ganguly A,Mucsi a D,et al.Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contactdependent lethargy.J Exp Med,2017,214(2):327-338
[11]Wei Lin Z F.Immunological synapse molecules.Journal of Immunobiology,2016,1(3):1000111(DOI:10001101004172/1002476-1001966)
[12]Wei Lin X W.Regulating Dcs in innate immune response and infection by cytoskeletal proteins.Journal of Immunobiology,2017,2(2):1000124(DOI:10001101004172/1002476-1001966)
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[15]Pulecio J,Tagliani E,Scholer A,et al.Expression of WiskottAldrich syndrome protein in dendritic cells regulates synapse formation and activation of naive CD8+T cells.J Immunol,2008,181(2):1135-1142
[16]Rodriguez-Fernandez J L,Riol-Blanco L,Delgado-Martin C.What is an immunological synapse?Microbes Infect,2010,12(6):438-445
[17]Thauland T J,Parker D C.Diversity in immunological synapse structure.Immunology,2010,131(4):466-472
[18]Monks C R,Freiberg B A,Kupfer H,et al.Three-dimensional segregation of supramolecular activation clusters in T cells.Nature,1998,395(6697):82-86
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[21]Rudd P M,Wormald M R,Stanfield R L,et al.Roles for glycosylation of cell surface receptors involved in cellular immune recognition.J Mol Biol,1999,293(2):351-366
[22]Lin W,Fan Z,Suo Y,et al.The bullseye synapse formed between CD4+T-cell and staphylococcal enterotoxin B-pulsed dendritic cell is a suppressive synapse in T-cell response.Immunol Cell Biol,2015,93(1):99-110
[23]Masi G,Baldari C T.Signaling at the immune synapse:vesicular trafficking takes the stage.Cell Mol Immunol,2013,10(6):459-462
[24]Dustin M L.Coordination of T cell activation and migration through formation of the immunological synapse.Ann N Y Acad Sci,2003,987:51-59
[25]Lin W,Suo Y,Deng Y,et al.Morphological change of CD4(+)T cell during contact with DC modulates T-cell activation by accumulation of F-actin in the immunology synapse.BMC Immunol,2015,16(49):1-15
[26]Yuanzhen Suo W L,Yuting Deng,Zhichao Fan,et al.ICAM-1depletion in the center of immunological synapses is important for calcium releasing in T-cells.Journal of Innovative Optical Health Sciences,2017,11(1):1750015
[27]Schneider H,Smith X,Liu H,et al.CTLA-4 disrupts ZAP70microcluster formation with reduced T cell/APC dwell times and calcium mobilization.Eur J Immunol,2008,38(1):40-47
[28]Chikuma S,Bluestone J A.CTLA-4 and tolerance:the biochemical point of view.Immunol Res,2003,28(3):241-253
[29]Chikuma S.CTLA-4,an Essential immune-checkpoint for T-cell activation.Curr Top Microbiol Immunol,2017,doi:101007/82_2017_61
[30]Bollyky P L,Evanko S P,Wu R P,et al.Th1 cytokines promote T-cell binding to antigen-presenting cells via enhanced hyaluronan production and accumulation at the immune synapse.Cell Mol Immunol,2010,7(3):211-220
[31]Takamatsu H,Okuno T,Kumanogoh A.Regulation of immune cell responses by semaphorins and their receptors.Cell Mol Immunol,2010,7(2):83-88
[32]Maldonado R A,Irvine D J,Schreiber R,et al.A role for the immunological synapse in lineage commitment of CD4lymphocytes.Nature,2004,431(7008):527-532
[33]Huse M,Lillemeier B F,Kuhns M S,et al.T cells use two directionally distinct pathways for cytokine secretion.Nat Immunol,2006,7(3):247-255
[34]Sanderson N S,Puntel M,Kroeger K M,et al.Cytotoxic immunological synapses do not restrict the action of interferon-gamma to antigenic target cells.Proc Natl Acad Sci USA,2012,109(20):7835-7840
[35]Xu X,Liu X,Long J,et al.Interleukin-10 reorganizes the cytoskeleton of mature dendritic cells leading to their impaired biophysical properties and motilities.PLo S One,2017,12(2):e0172523
[36]Cavrois M,Neidleman J,Greene W C.The achilles heel of the trojan horse model of HIV-1 trans-infection.PLo S Pathog,2008,4(6):e1000051
[37]Do T,Murphy G,Earl L A,et al.Three-dimensional imaging of HIV-1 virological synapses reveals membrane architectures involved in virus transmission.J Virol,2014,88(18):10327-10339
[38]Yu H J,Reuter M A,Mcdonald D.HIV traffics through a specialized,surface-accessible intracellular compartment during trans-infection of T cells by mature dendritic cells.PLo S Pathog,2008,4(8):e1000134
[39]Sewald X,Ladinsky M S,Uchil P D,et al.Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection.Science,2015,350(6260):563-567
[40]Akula S M,Naranatt P P,Walia N S,et al.Kaposi's sarcoma-associated herpesvirus(human herpesvirus 8)infection of human fibroblast cells occurs through endocytosis.J Virol,2003,77(14):7978-7990
[41]Naranatt P P,Krishnan H H,Smith M S,et al.Kaposi's sarcoma-associated herpesvirus modulates microtubule dynamics via Rho A-GTP-diaphanous 2 signaling and utilizes the dynein motors to deliver its DNA to the nucleus.J Virol,2005,79(2):1191-1206
[42]Sharma-Walia N,Naranatt P P,Krishnan H H,et al.Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 envelope glycoprotein g B induces the integrin-dependent focal adhesion kinase-Src-phosphatidylinositol 3-kinase-rho GTPase signal pathways and cytoskeletal rearrangements.J Virol,2004,78(8):4207-4223
[43]Papa I,Saliba D,Ponzoni M,et al.TFH-derived dopamine accelerates productive synapses in germinal centres.Nature,2017,547(7663):318-323
[44]Qi H.Immunology:Nervous crosstalk to make antibodies.Nature,2017,547(7663):288-290
[45]Lukyanov K A,Chudakov D M,Lukyanov S,et al.Innovation:Photoactivatable fluorescent proteins.Nat Rev Mol Cell Biol,2005,6(11):885-891
[46]Patterson G H,Lippincott-Schwartz J.A photoactivatable GFP for selective photolabeling of proteins and cells.Science,2002,297(5588):1873-1877
[47]Ando R,Hama H,Yamamoto-Hino M,et al.An optical marker based on the UV-induced green-to-red photoconversion of a fluorescent protein.Proc Natl Acad Sci USA,2002,99(20):12651-12656
[48]Tsutsui H,Karasawa S,Shimizu H,et al.Semi-rational engineering of a coral fluorescent protein into an efficient highlighter.EMBO Rep,2005,6(3):233-238
[49]Victora G D,Schwickert T A,Fooksman D R,et al.Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter.Cell,2010,143(4):592-605
[50]Ghigo C,Mondor I,Jorquera A,et al.Multicolor fate mapping of Langerhans cell homeostasis.J Exp Med,2013,210(9):1657-1664
[51]Jarjour M,Jorquera A,Mondor I,et al.Fate mapping reveals origin and dynamics of lymph node follicular dendritic cells.J Exp Med,2014,211(6):1109-1122
[52]Snippert H J,Van Der Flier L G,Sato T,et al.Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells.Cell,2010,143(1):134-144
[53]Tischbirek C H,Birkner A,Konnerth A.In vivo deep two-photon imaging of neural circuits with the fluorescent Ca2+indicator Cal-590.J Physiol,2016,595(10):3097-3105
[54]Roxbury D,Jena P V,Williams R M,et al.Hyperspectral microscopy of near-infrared fluorescence enables 17-chirality carbon nanotube imaging.Sci Rep,2015,21(5):14167
[55]Ingulli E,Mondino A,Khoruts A,et al.In vivo detection of dendritic cell antigen presentation to CD4(+)T cells.J Exp Med,1997,185(12):2133-2141
[56]Beemiller P,Jacobelli J,Krummel M F.Integration of the movement of signaling microclusters with cellular motility in immunological synapses.Nat Immunol,2012,13(8):787-795
[57]Stoll S,Delon J,Brotz T M,et al.Dynamic imaging of T cell-dendritic cell interactions in lymph nodes.Science,2002,296(5574):1873-1876
[58]Marangoni F,Murooka T T,Manzo T,et al.The transcription factor NFAT exhibits signal memory during serial T cell interactions with antigen-presenting cells.Immunity,2013,38(2):237-249
[59]Moreau H D,Lemaitre F,Terriac E,et al.Dynamic in situ cytometry uncovers T cell receptor signaling during immunological synapses and kinapses in vivo.Immunity,2012,37(2):351-363
[2]Grakoui A,Bromley S K,Sumen C,et al.The immunological synapse:a molecular machine controlling T cell activation.Science,1999,285(5425):221-227
[3]Lee K H,Holdorf a D,Dustin M L,et al.T cell receptor signaling precedes immunological synapse formation.Science,2002,295(5559):1539-1542
[4]Lee K H,Dinner a R,Tu C,et al.The immunological synapse balances T cell receptor signaling and degradation.Science,2003,302(5648):1218-1222
[5]Lee S J,Hori Y,Groves J T,et al.The synapse assembly model.Trends Immunol,2002,23(10):500-502
[6]Friedman R S,Beemiller P,Sorensen C M,et al.Real-time analysis of T cell receptors in naive cells in vitro and in vivo reveals flexibility in synapse and signaling dynamics.J Exp Med,2010,207(12):2733-2749
[7]Hugues S,Fetler L,Bonifaz L,et al.Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity.Nat Immunol,2004,5(12):1235-1242
[8]Shakhar G,Lindquist R L,Skokos D,et al.Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo.Nat Immunol,2005,6(7):707-714
[9]Yan J,Liu B,Shi Y,et al.Class II MHC-independent suppressive adhesion of dendritic cells by regulatory T cells in vivo.J Exp Med,2017,214(2):319-326
[10]Chen J,Ganguly A,Mucsi a D,et al.Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contactdependent lethargy.J Exp Med,2017,214(2):327-338
[11]Wei Lin Z F.Immunological synapse molecules.Journal of Immunobiology,2016,1(3):1000111(DOI:10001101004172/1002476-1001966)
[12]Wei Lin X W.Regulating Dcs in innate immune response and infection by cytoskeletal proteins.Journal of Immunobiology,2017,2(2):1000124(DOI:10001101004172/1002476-1001966)
[13]Suzuki J,Yamasaki S,Wu J,et al.The actin cloud induced by LFA-1-mediated outside-in signals lowers the threshold for T-cell activation.Blood,2007,109(1):168-175
[14]Bouma G,Mendoza-Naranjo A,Blundell M P,et al.Cytoskeletal remodeling mediated by WASp in dendritic cells is necessary for normal immune synapse formation and T-cell priming.Blood,2011,118(9):2492-2501
[15]Pulecio J,Tagliani E,Scholer A,et al.Expression of WiskottAldrich syndrome protein in dendritic cells regulates synapse formation and activation of naive CD8+T cells.J Immunol,2008,181(2):1135-1142
[16]Rodriguez-Fernandez J L,Riol-Blanco L,Delgado-Martin C.What is an immunological synapse?Microbes Infect,2010,12(6):438-445
[17]Thauland T J,Parker D C.Diversity in immunological synapse structure.Immunology,2010,131(4):466-472
[18]Monks C R,Freiberg B A,Kupfer H,et al.Three-dimensional segregation of supramolecular activation clusters in T cells.Nature,1998,395(6697):82-86
[19]Dustin M L,Chakraborty a K,Shaw a S.Understanding the structure and function of the immunological synapse.Cold Spring Harb Perspect Biol,2010,2(10):a002311
[20]Gonzalez P A,Carreno L J,Figueroa C A,et al.Modulation of immunological synapse by membrane-bound and soluble ligands.Cytokine Growth Factor Rev,2007,18(1-2):19-31
[21]Rudd P M,Wormald M R,Stanfield R L,et al.Roles for glycosylation of cell surface receptors involved in cellular immune recognition.J Mol Biol,1999,293(2):351-366
[22]Lin W,Fan Z,Suo Y,et al.The bullseye synapse formed between CD4+T-cell and staphylococcal enterotoxin B-pulsed dendritic cell is a suppressive synapse in T-cell response.Immunol Cell Biol,2015,93(1):99-110
[23]Masi G,Baldari C T.Signaling at the immune synapse:vesicular trafficking takes the stage.Cell Mol Immunol,2013,10(6):459-462
[24]Dustin M L.Coordination of T cell activation and migration through formation of the immunological synapse.Ann N Y Acad Sci,2003,987:51-59
[25]Lin W,Suo Y,Deng Y,et al.Morphological change of CD4(+)T cell during contact with DC modulates T-cell activation by accumulation of F-actin in the immunology synapse.BMC Immunol,2015,16(49):1-15
[26]Yuanzhen Suo W L,Yuting Deng,Zhichao Fan,et al.ICAM-1depletion in the center of immunological synapses is important for calcium releasing in T-cells.Journal of Innovative Optical Health Sciences,2017,11(1):1750015
[27]Schneider H,Smith X,Liu H,et al.CTLA-4 disrupts ZAP70microcluster formation with reduced T cell/APC dwell times and calcium mobilization.Eur J Immunol,2008,38(1):40-47
[28]Chikuma S,Bluestone J A.CTLA-4 and tolerance:the biochemical point of view.Immunol Res,2003,28(3):241-253
[29]Chikuma S.CTLA-4,an Essential immune-checkpoint for T-cell activation.Curr Top Microbiol Immunol,2017,doi:101007/82_2017_61
[30]Bollyky P L,Evanko S P,Wu R P,et al.Th1 cytokines promote T-cell binding to antigen-presenting cells via enhanced hyaluronan production and accumulation at the immune synapse.Cell Mol Immunol,2010,7(3):211-220
[31]Takamatsu H,Okuno T,Kumanogoh A.Regulation of immune cell responses by semaphorins and their receptors.Cell Mol Immunol,2010,7(2):83-88
[32]Maldonado R A,Irvine D J,Schreiber R,et al.A role for the immunological synapse in lineage commitment of CD4lymphocytes.Nature,2004,431(7008):527-532
[33]Huse M,Lillemeier B F,Kuhns M S,et al.T cells use two directionally distinct pathways for cytokine secretion.Nat Immunol,2006,7(3):247-255
[34]Sanderson N S,Puntel M,Kroeger K M,et al.Cytotoxic immunological synapses do not restrict the action of interferon-gamma to antigenic target cells.Proc Natl Acad Sci USA,2012,109(20):7835-7840
[35]Xu X,Liu X,Long J,et al.Interleukin-10 reorganizes the cytoskeleton of mature dendritic cells leading to their impaired biophysical properties and motilities.PLo S One,2017,12(2):e0172523
[36]Cavrois M,Neidleman J,Greene W C.The achilles heel of the trojan horse model of HIV-1 trans-infection.PLo S Pathog,2008,4(6):e1000051
[37]Do T,Murphy G,Earl L A,et al.Three-dimensional imaging of HIV-1 virological synapses reveals membrane architectures involved in virus transmission.J Virol,2014,88(18):10327-10339
[38]Yu H J,Reuter M A,Mcdonald D.HIV traffics through a specialized,surface-accessible intracellular compartment during trans-infection of T cells by mature dendritic cells.PLo S Pathog,2008,4(8):e1000134
[39]Sewald X,Ladinsky M S,Uchil P D,et al.Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection.Science,2015,350(6260):563-567
[40]Akula S M,Naranatt P P,Walia N S,et al.Kaposi's sarcoma-associated herpesvirus(human herpesvirus 8)infection of human fibroblast cells occurs through endocytosis.J Virol,2003,77(14):7978-7990
[41]Naranatt P P,Krishnan H H,Smith M S,et al.Kaposi's sarcoma-associated herpesvirus modulates microtubule dynamics via Rho A-GTP-diaphanous 2 signaling and utilizes the dynein motors to deliver its DNA to the nucleus.J Virol,2005,79(2):1191-1206
[42]Sharma-Walia N,Naranatt P P,Krishnan H H,et al.Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 envelope glycoprotein g B induces the integrin-dependent focal adhesion kinase-Src-phosphatidylinositol 3-kinase-rho GTPase signal pathways and cytoskeletal rearrangements.J Virol,2004,78(8):4207-4223
[43]Papa I,Saliba D,Ponzoni M,et al.TFH-derived dopamine accelerates productive synapses in germinal centres.Nature,2017,547(7663):318-323
[44]Qi H.Immunology:Nervous crosstalk to make antibodies.Nature,2017,547(7663):288-290
[45]Lukyanov K A,Chudakov D M,Lukyanov S,et al.Innovation:Photoactivatable fluorescent proteins.Nat Rev Mol Cell Biol,2005,6(11):885-891
[46]Patterson G H,Lippincott-Schwartz J.A photoactivatable GFP for selective photolabeling of proteins and cells.Science,2002,297(5588):1873-1877
[47]Ando R,Hama H,Yamamoto-Hino M,et al.An optical marker based on the UV-induced green-to-red photoconversion of a fluorescent protein.Proc Natl Acad Sci USA,2002,99(20):12651-12656
[48]Tsutsui H,Karasawa S,Shimizu H,et al.Semi-rational engineering of a coral fluorescent protein into an efficient highlighter.EMBO Rep,2005,6(3):233-238
[49]Victora G D,Schwickert T A,Fooksman D R,et al.Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter.Cell,2010,143(4):592-605
[50]Ghigo C,Mondor I,Jorquera A,et al.Multicolor fate mapping of Langerhans cell homeostasis.J Exp Med,2013,210(9):1657-1664
[51]Jarjour M,Jorquera A,Mondor I,et al.Fate mapping reveals origin and dynamics of lymph node follicular dendritic cells.J Exp Med,2014,211(6):1109-1122
[52]Snippert H J,Van Der Flier L G,Sato T,et al.Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells.Cell,2010,143(1):134-144
[53]Tischbirek C H,Birkner A,Konnerth A.In vivo deep two-photon imaging of neural circuits with the fluorescent Ca2+indicator Cal-590.J Physiol,2016,595(10):3097-3105
[54]Roxbury D,Jena P V,Williams R M,et al.Hyperspectral microscopy of near-infrared fluorescence enables 17-chirality carbon nanotube imaging.Sci Rep,2015,21(5):14167
[55]Ingulli E,Mondino A,Khoruts A,et al.In vivo detection of dendritic cell antigen presentation to CD4(+)T cells.J Exp Med,1997,185(12):2133-2141
[56]Beemiller P,Jacobelli J,Krummel M F.Integration of the movement of signaling microclusters with cellular motility in immunological synapses.Nat Immunol,2012,13(8):787-795
[57]Stoll S,Delon J,Brotz T M,et al.Dynamic imaging of T cell-dendritic cell interactions in lymph nodes.Science,2002,296(5574):1873-1876
[58]Marangoni F,Murooka T T,Manzo T,et al.The transcription factor NFAT exhibits signal memory during serial T cell interactions with antigen-presenting cells.Immunity,2013,38(2):237-249
[59]Moreau H D,Lemaitre F,Terriac E,et al.Dynamic in situ cytometry uncovers T cell receptor signaling during immunological synapses and kinapses in vivo.Immunity,2012,37(2):351-363