医学免疫学课件：免疫突触和hiv

1、immunological synapseand HIV1.immunological synapseCONCEPT/ ISIMMUNOLOGICAL SYNAPSEThe closely apposed region plasma membrane in the interaction between T cells and antigen-presenting cells, centered on interacting TCRs and MHCpeptide complexes. HISTORY/ ISAbraham Kupfer , 1995three-dimensional imag

2、es of immune cells interacting with one another.Daniel Davis and Jack Stromingerstructured immune synapses for a different lymphocyte, the Natural Killer cellSTRUCTURE/ IST-CELLAPCBulls-eyeTCR-MHCADHERENTYROSINKINASEFigure 1 Color-enhanced reconstruction of an immunological synapse David Male. Immun

3、ologyM. ELSEVIER. 2013，P.151STRUCTURE/ IS“lamellipodium”LFA-1, “lamellum”endo-cSMAC:CD28-enhanced TCR signaling complexes exo-cSMAC:TCR-enriched extracellular vesicles dSMACpSMACcSMACFigure 2 Model immunological synapseelevated (A) and front-on view (B) of model for synapse focusing on interface The

4、 Immunological Synapse. Cancer Immunol Res 2014; 2(11):1022-33STRUCTURE/ IS“lamellipodium”LFA-1, “lamellum”endo-cSMAC:CD28-enhanced TCR signaling complexes exo-cSMAC:TCR-enriched extracellular vesicles dSMACpSMACcSMACThe Immunological Synapse. Cancer Immunol Res 2014; 2(11):1022-33Figure 3 SMACs and

5、 representative receptor classes in immunological synapse. FORMATION/ ISDynamic processMicrocluster: TCR and CD28From dSMAC to cSMACF-actin in pSMAC and dSMACassisted by LFA-1 ICAM-1 FUNCTION/ ISMHC peptide - TCR(CD4+ - MHCII)coreCo-stimulator/INHIBITORB7 - CD28B7 - CTLA-4/PD-1adhesionICAM-1 - LFA-1

6、David Male. ImmunologyM. ELSEVIER. 2013，P.152Figure 4 Molecular interactions in the immunological synapse FUNCTION/ ISFunction of immunological synapse：priming of responses in which the T cell is receiving information;effector functions in which the T cell is sending information. FUNCTION/ ISDavid M

7、ale. ImmunologyM. ELSEVIER. 2013，P.153Figure 5 Dual signaling is necessary for full T cell activation FUNCTION/ ISCD2：sustains antigen-induced Ca2+ increase in T cells contributes to the generation of TCR triggered microdomains in the membrane that recruit signaling molecules like Lck and LAT play a

8、 direct role in T-cell signaling via multiple polyproline motifs that activate kinases such as FynFUNCTION/ ISFigure 6 Intracellular signaling in T cell activation David Male. ImmunologyM. ELSEVIER. 2013，P.153FUNCTION/ ISLCK / Fyncd3itamZap-70latnfatNf-kBAp-1Il-2LCKClustering of surface receptors su

9、ch as TCR, CD4, CD28, and CD45 results in activation of tyrosine kinases CD4, which is associated with the TCR complex, binds to the LCKPhosphorylate the ITAM domains on the g chains of CD3 2.HIVCD4+ TCDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus - This media comes from the C. Goldsmith

10、 Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus - This media comes from the Centers for Disease Control and Preventions Public Health Image Library (PHIL)Figure 7 Scanning electron micrograph of HIV-1 budding (in green) from cultured lymphocyte.PATHOGENESIS/ HIVInfecti

11、on with HIV renders cells hyper-responsive to stimulation: increased IL-2 production Nef limits this process, in part, by manipulating the formation of immunological synapses. PATHOGENESIS/ HIVNefNecessary in HIV replicationImmunological synapseChange in surface proteinInduce TCR signaling TCR remai

12、n in vesicles Induce tyrosine phosphorylate prevent hyper production of IL-2impact on TCR and LCK Fate of TCR:UNENGAGEDInternalized RecycleENGAGEDTowards the immunological synapseAccumulate and form microclustersDegradationtcrlckimpact on TCR and LCK Slow internalization Slow polarized movementRemai

13、n in endosomeFigure 8 HIV-1 impairs the formation of the immunological syn- apse: impact on TCR and LCK Modulation of the immunological synapse: a key to HIV-1 pathogenesis? . Nature Publishing Group 2007; 7:310-317F-actinnefalter t-cell actin dynamicn-WASP: Actin remodelling SH3 binding motifFigure

14、 9 HIV-1 downmodulates actin cytoskeleton dynamics at the immunological synapse. Modulation of the immunological synapse: a key to HIV-1 pathogenesis? . Nature Publishing Group 2007; 7:310-317 CTLA-4 reduce the contact time between T cell and APC. reduce the contact area at the immunological synapse

15、 reduction in Ca2+ mobilization and IL-2 production significant inhibition of HIV replication. downregulate expression of CTLA-4 PATHOGENESIS/ HIVWhat might be the advantage for HIV-1 of modulating actin dynamics and immunological synapse architecture and function? PATHOGENESIS/ HIVBALANCEReplicatio

16、n vs. Cell deathactivated effector quiescent memory cell NEFImpairs apoptotic signalsprevents recognition virological synapse establishment of HIV latencygenerating and maintaining a long-lived cellular reservoir for the virus promote viral disseminationwithout requiring either CXCR4 or CCR5 corecep

17、tor molecules IMMUNOLOGICAL SYNAPSEVIROLOGICAL SYNAPSEvirological synapse ISVSCD4+ T and APCinfected and uninfected CD4+ T cells TCRpeptide MHC interaction gp120 and CD4Several hours60 minpSMAC: LFA-1 ICAM-1 TCR signaling cascadeActin remodeling virological synapse virological synapse Immunological

18、synapse Figure 10 Model of virological and immunological synapse formation in the contribution to HIV persistence The immunological synapse: the gateway to the HIV reservoir. Immunological Reviews 2013. 254: 305325virological synapse Free HIV-1 particles, even in large quantities, are unable to trig

19、ger pyroptosis The fundamental killing units of CD4 T cells are infected cells, not the virus Figure 11 Cell-to-Cell Transmission of HIV-1 Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue- Derived CD4 T Cells. Cell Reports 2015. 12: 15551563 FORECAST/ HIV

20、As the precise mechanisms of HIV latency establishment and maintenance become clearer, interventions that disrupt specific components of the immunological synapse may represent the final step in the process of HIV eradication. REFERENCEArash G, Shannon K. B, Cenk S, et al. The Immunological Synapse:

21、 A Molecular Machine Controlling T Cell Activation . SCIENCE.1999;285(9):221-227Oliver T. Fackler, Andres Alcover and Olivier Schwartz. Modulation of the immunological synapse: a key to HIV-1 pathogenesis? . Nature Publishing Group. 2007; 7:310-317Deanna A. Kulpa Jessica H. The immunological synapse

22、: the gateway to the HIV reservoir. Immunological Reviews. 2013; 254: 305325Michael L. Dustin. The Immunological Synapse. Cancer Immunol Res. 2014; 2(11):1023-1033Michael L. Dustin, Arup K. Chakraborty, and Andrey S. Shaw. Understanding the Structure and Function of the Immunological Synapse. Cold Spring Harb Perspect Biol 2010;2:a002311 Nicole L.K. Galloway, Gilad Doitsh, Kathryn M. Monroe, et al. Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue- Derived CD4 T Cells. Cell Reports. 2015;12:15551563David Male. ImmunologyM. ELSEVIER. 20