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8.  Natural killer cells , their characteristics and function . Interferons .

8.  Natural killer cells , their characteristics and function . Interferons . 9. HLA system   ( classes , polymorphism , typing ). 10.  Binding of peptides to MHC. Antigen presentation ( function , purpose ).

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8.  Natural killer cells , their characteristics and function . Interferons .

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  1. 8. Naturalkillercells, theircharacteristicsandfunction. Interferons. 9. HLA system  (classes, polymorphism, typing). 10. Bindingofpeptides to MHC. Antigen presentation (function, purpose). 11. T-lymphocytes, ontogenesis, selection, surfacemarkers, subpopulations, functions). 12. Th1 basedimmunereaction. 13. Th2 basedimmunereaction. 14. Tcbasedimmunereaction.

  2. NK cellsInterferons

  3. NK cells lymphoidcellswhichbelon to innateimmunity killcellswhichhaveabnormallylowMHCgpIexpression(some tumor and virus infectedcells) havesimilarcytotoxicmechanisms as Tc NK cellsactivators - IFNa, IFNb

  4. NK cellsreceptors • Activatingreceptors • Somesurfacelectins • Fcreceptor CD16 • Inhibitory receptors- recognizeMHC gpI • Imunoglobulin family - KIR (killercell immunoglobulin likereceptors) • C-type lektinfamily - eg CD94/NKG2

  5. ADCC (antibody-dependentcellular cytotoxicity) • NK cellsexpress CD16whichrecognizeFc part ofIgGantibodiesattached to thesurfaceof a cell, thisleads to theactivationofNK cell cytotoxicmechanisms

  6. NK cell cytotoxicmechanisms • Cytotoxicgranules (perforinsandgranzymes) • Fas ligand • TNFa

  7. Interferons • IFNa- produced by virus infectedlymphocytes, monocytesandmacrophages • IFNb - produced by virus-infectedfibroblastsandepithelialcells • IFNaandIFNb - bind to receptors on thesurfaceofinfectedandhealthycellsandinduce in themanantiviralstate(synthesisofenzymesthatblockviralreplication in the cell); NK activation, ↑ HLA I expression • IFNg- produced by TH1 cells, regulatoryfunction, activatesmacrophages (NO synthase, NADPH oxidase), ↑HLA expression

  8. Interferons

  9. HLA system (MHC glycoproteins)

  10. MHC glycoproteinsclass I (Major histocompatibilitycomplex) • MHCgpIpresentpeptide fragmentsfromitracellularproteins(which are produced by cell, includingviralpeptidesif are present) on the cell surfaceforcytotoxic T lymphocytes( CD8+) • Expressedon allnucleatedcells • 3 isotypesofclassical MHC gp. (HLA - A,-B,-C) • 3 isotypes non-classical MHC gp. (HLA - E,-F,-G; molecule CD1)

  11. MHC gp I structure • MHC gpclass I consistsoftransmembranechain a and associatedb2microglobulin • a1, a2 - bindingsiteforpeptides • Peptide bindingis necessary for a stable conformation ofMHCgp

  12. MHC gpI peptide presentation • MHC gp I bindspeptideslong8 - 10 aminoacids • CertainMHC gpmoleculebindspeptidessharingidenticalstructuralfeaturesbindingmotif • Thebindingofendogenouspeptidesoccurs in theendoplasmicreticulumduringbiosynthesisof MHC gp I • These peptides are produced from intracellularproteins that are cleaved by theproteasomes

  13. MHC gpI peptide presentation

  14. Non-classical MHC gp I • HLA - E,-F,-G; CD1 molecules • Structurallysimilar to classical MHC gp • Lesspolymorphic • Expressedonly on somecells • Theyspecialize in bindingofspecificligands

  15. Non-classical MHC gp I • HLA-EandHLA-G- expressedon thetrophoblastcells • Complexesof HLA-E and HLA-G withpeptides are recognized by NK cells inhibitory receptorsandcontribute to the tolerance ofthe fetus in utero

  16. MHC glycoproteinsclass II • MHC gpIIpresentpeptide fragmentsfromextracellularproteinson the cell surfaceforhelperT lymphocytes(CD4+) • Expressedon theAPC (dendriticcells, monocytes, macrophages, B lymphocytes) • 3 isotypesof MHC gpII (DR, DQ, DP)

  17. MHC gp IIstructure • MHC gp II consistof 2 associatedtransmembranechainsaandb • a1, b1 -bindingsitefor peptide • Peptide bindingisnecessaryfor a stablecoformationof MHC gpandensureitslongpresentation on the cell surface

  18. MHC gp II peptide presentation • MHC gp II bindspeptideslong15 - 35 aminoacids • Certain MHC gpmoleculebindspeptidessharingidenticalstructuralfeatures–bindingmotif • Invariant chainblocksthebindingsiteforthepeptide • Exogenouspeptidesbinds to MHC gp II in theendosome • Peptide fragmentsfromendocytosedextracellularproteins

  19. MHC gp II peptide presentation

  20. Antigen prezentation An antigen-presenting cell (APC) process foreignantigensandpresentthemcomplexed withMHC‘s on their surfaces to T cells.

  21. MHC glycoproteinspolymorphism • HLA complexislocated on chromosome 6 • For MHC gpistypicalhighpolymorphism(hundredsofdifferentalelicformsofisotypes) • Codominant inheritance ofalelicforms

  22. MHC glycoproteinspolymorphism • Increasesresistance to disease • Causescomplications in the organ transplantation • Association of certain alleles with autoimmune diseases and increased susceptibility to infections

  23. HLA typing(determminationof HLA antigens on thesurfaceoflymphocytes) • Carryoutduringthetestingbeforetransplantation, in paternity determination • Serotyping • Genotyping • PCR-SSP • PCR-SSO • PCR-SBT

  24. T cells

  25. T cells • Cellularcomponentof antigen-specificmechanisms • Regulationofimmuneprocessesanddestructionof virus-infectedcellsor tumor cells • Severalsubsetsof T lymphocytes (TH1, TH2, Treg, TC…) • TCR recognize peptide-MHC complex • T cell are activated by APC

  26. T cell development • T cellsoriginate in bone marrowandthenmigrate to thethymuswheretheymature (ab T lymphocytes), thefinaldifferentiationisaftertheactivationby antigen processedandpresented by APC • gdT cellscandevelopoutsidethethymus (the minority population) • T cells are stimulatedafteractivation to proliferateanddifferentiateintoeffectorcellsandmemorycells

  27. T cell development

  28. T cell development Pluripotenthematopoietic stem cells Pro-thymocytes– double negative T cells- are comingfromthe bone marrow to thethymus, wheretheybegin to rearrangeTCRbgenes, express on theirsurfacepre-TCR (Composedofbchain, pre-TCRaand CD3 complex), thenbeginTCRagenesrearrangement Corticalthymocytes – double positive T cells- express on theirsurfaceTCR (composedofchainsa, b and CD3) andCD4 and CD8 co-receptor (double positive T lymphocyte), selectionofthecellswithdysfunctional TCR andautoreactivecellsMedullarythymocytes (mature T cell) - retaintheexpressionofCD4 or CD8, thenmigrate to thesecondarylymphoidorgans MatureT cells(Medullarythymocytes) leavethethymusandmigrate to secondarylymphoidorgans

  29. T cell selection • Positive selection- theeliminationofcellswithdysfunctional TCR, thymocytesthatrecognize MHC gpwithlowaffinity are positivelyselected, thenmaintaintheexpressionof CD4 or CD8 (dependingwhichclassof MHC gpbinds to the TCR). • Negative selection- theeliminationofautoreactivecells, whichstronglybindMHCgpwithnormalpeptides (autoantigens) which are expressed on thesurfaceofthymiccells • 98% of pro-thymocytes in thethymusduringitsdevelopmentdies

  30. T cell surfacemarkers • TCR - recognizesAgpeptide bound to MHC molecule • CD3 - TCR component, participatesin signaltransduction • CD4orCD8 - co-receptors, bindto MHC gp • CD28 - costimulatory receptor, binds to CD80, CD86 on APC • CTLA-4 (CD152) - inhibitory receptor, binds to CD80, CD86

  31. T cell subpopulations • abT lymphocytes- haveTCRab, major type (95-98%), needthymusfordevelopment, recognize peptide antigens in thecomplexwith MHC gp • gdT lymphocytes- (2-5%) maydevelopoutsidethethymus, some are able to recognizenativeAg, apply in defense ofthe skin andmucousmembranes

  32. CD4+ T cells Express theCD4 coreceptor(co-receptor for MHC class II gp), TCRab, precursorsofhelper T cells (TH),THdifferentiate to severalsubtypes, whichsecretdifferentcytokines TH0 - produce a mixtureofcytokines such as TH1 and TH2 TH1 - IL-2, IFNg(activatesmacrophages ) TH2 - IL-4, IL-5, IL-6, IL-10 (B lymphocytesassistance) TH3– TGFb Treg - regulatory T cellsarise in thethymusfrom a part ofautoreactivelymphocytes, suppresstheactivityofautoreactive T cell clones (IL-10, TGFb)

  33. CD8+ T cells Expressingthe CD8 co-receptor(co-receptor for MHC gpI), TCRab,precursorsofcytotoxic T cells (TC) TC– recognizeanddestroy virus –infectedcellsorthecellsinfectedwithotherintracellularparasitesandsomecancercells

  34. TCR • TCR (T cell receptor) isheterodimerconsistingofaandb (g,d) chains • associatedwithCD3 complex, whichisnecessaryforsignaltransduction • N-terminalpartsofaandb (g,d) chainsformthebindingsiteforAg

  35. T cell activation • T cell are activated by APC (DC, monocyte, macrophage, B cell) • TCRrecognizepeptide-MHC complex • TCR cooperatewithcoreceptors CD4 (binds to MHC gp II) or CD8 (binds to MHC gp I)

  36. T cell activation Signal:TCR– MHC gpI / II +Agpeptid (APC) Co-stimulatingsignal: CD 28 (T lymphocyte) – CD 80, CD 86 (APC) (Without costimulation, the T cell becomes anergic)

  37. Th1 and Th2 basedimmunereaction

  38. TH1 basedimmune response

  39. TH1 basedimmuneresponse - inflammatoryreaction • TH1 cellscooperatewithmacrophagesandactivatethem(NO production - destroyintracellularparasites) • Activatedmacrophagessecretesomecytokines (IL-1, TNF, ...) that help to stimulate T cellsandlocalinflammation • Interactionbetween TH1 cellsandmacrophagesis a fundamentalmechanismofdelayed-type immunopathologicalreactions (DTH Delayed-type hypersensitivity)

  40. TH1 basedimmune response • Theinfectedmacrophageproduces protein fragmentsderivedfromintracellularparasites, someofthemare presented on themacrophagesurfacein thecomplexwithMHC gpclass II • Macrophagesanddendriticcellsstimulatedby certainmicroorganismsproduceIL-12 • THprecursor, whichdetectstheinfectedmacrophageandreceivessignals via theTCR, CD 28 andreceptor for IL-12 proliferatesanddifferentiatesintoeffectorTH1 cellsthatproduceIFNgandIL-2. • IFNgactivatesmacrophage NO synthaseIL-2isgrowthfactorforT cells

  41. Interactionbetween APC and THprecursor

  42. TH2 basedimmune response

  43. TH2 basedimmune response • TH2 cellscooperatewith B lymphocytes(whichwerestimulated by Ag) by cytokineproduction (IL-4, IL-5, IL-6, IL-10) anddirectintercellularcontact(CD 40L) • Forstimulationof B lymphocytesisusuallynecessarycooperationbetween APC → TH2 cell → B lymphocyte • In minimal model, wherethe B cell becomes a good APC (CD80, CD86) issufficientcooperationbetween TH2 cell → B lymphocyte

  44. TH2 basedimmune response • THprecursor, whichdetectstheinfectedmacrophageandreceivessignalsthroughtheTCR, CD 28 , IL-4 receptorand IL-2 receptor proliferatesanddifferentiates in theeffector TH2, whichprovide B lymphocytesauxiliarysignals via secretedcytokinesIL-4, IL-5, IL-6, IL-10 andmoleculeCD 40L, whichbind to thecostimulatory receptor on B lymphocytes CD 40

  45. TH2 basedimmune response • Interactionbetween CD40 (B lymphocytes) and CD40L (TH2 cells) isessentialfortheinitiationofsomaticmutations, izotypeswitchingandformationofmemorycells • IL-4, IL-5, IL-6, IL-10: stimulationof B lymphocytes

  46. FunctionofTH2 cells

  47. Mutualregulationofactivities TH1versus TH2 • Whetherthe THprecursor cell willdevelopinto TH1 or TH2 decidescytokineratio of IL-12 and IL-4 • IL-12isproduced by macrophagesanddendriticcellsstimulated by certainmicroorganisms • IL-4isproduced by activatedbasophils, mast cellsand TH2 cells • TH1 cytokines (mainlyIFNg) inhibitthedevelopmentof TH2 andstimulatethedevelopmentof TH1 (IL-2 stimulatesalso TH2) • Cytokinesproduced by TH2 (IL-4, IL-10) inhibitthedevelopmentof TH1 andstimulatethedevelopmentof TH2

  48. TCbasedimmune response

  49. Cytotoxic T lymphocytesstimulation • TCrecognizecellsinfectedwithvirusesorotherintracellularparasites, andsome tumor cells • Precursorof TC, whichrecognizes a peptide-MHC gpIcomplexon thesurfaceof APC via TCRandreceivessignals via CD 28 proliferatesanddifferentiates to clonematureeffectorcytotoxiccells (CTL) • Forfull TC activationisnecessary IL-12 • CTL are spread by bloodstreamintotissues; foractivationofcytotoxicmechanismsissufficientsignalvia TCR

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