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

9. Natural killer cells , their characteristics and function . Interferons . 1 0.  HLA system   ( classes , polymorphism , typing ). 11. Binding of peptides to MHC. Antigen presentation ( function , purpose ).

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

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  1. 9.Naturalkillercells, theircharacteristicsandfunction. Interferons. 10. HLA system  (classes, polymorphism, typing). 11.Bindingofpeptides to MHC. Antigen presentation (function, purpose). 12. T-lymphocytes, ontogenesis, selection, surfacemarkers, subpopulations, functions). 13. Th1 basedimmunereaction. 14. Th2 basedimmunereaction. 15.Tcbasedimmunereaction. 16. Physiologicalmechanismsofregulationoftheimmunesystem.Cytokines (classificationaccording to thefunction).

  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 cells express CD16whichrecognizeFc part ofIgGantibodiesattached to thesurfaceof a cell, thisleads to theactivationof NK cell cytotoxicmechanisms

  6. NK cell cytotoxicmechanisms • Cytotoxicgranules (perforinsandgranzymes) • Fas ligand • TNFa • https://www.youtube.com/watch?v=HNP1EAYLhOs

  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 class I presentationendogenouspathway • MHC classI bindspeptideslong8 - 10 aminoacids • CertainMHC gpmoleculebindspeptidessharingidenticalstructuralfeatures - bindingmotif • Thebindingofendogenouspeptidesin theendoplasmicreticulumduringbiosynthesisof MHC class I protein • Peptides are produced from intracellularproteins degradatedby theproteasome https://www.youtube.com/watch?v=hzET2XMMW28

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

  14. 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

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

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

  17. MHC classII presentation • MHC class II bindspeptideslong15 - 35 aminoacids • Certain MHC gpmoleculebindspeptidessharingidenticalstructuralfeatures–bindingmotif • Invariant chainblocksthebindingsiteforthepeptide • The antigenic peptides are derived from extracellular proteins • Exogenouspeptidesbinds to MHC class II in theendosome • https://www.youtube.com/watch?v=8krIaGVR6Gk

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

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

  20. T cells

  21. 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

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

  23. T cell development Pluripotenthematopoietic stem cells Lymphoidprogenitors - are comingfromthe bone marrow to thethymus Pro-thymocytes– double negative T cells- begin to rearrangeTCRbgenes, express on theirsurfacepre-TCR(Composedofbchain, pre-TCRaand CD3 complex), thenbeginTCRagenesrearrangement Corticalthymocytes – double positive T cells- express on theirsurfaceTCRandCD4 and CD8 co-receptor (double positive T lymphocyte), T cell selection Medullarythymocytes - single positive T cells - retaintheexpressionofCD4 or CD8, thenmigrate to thesecondarylymphoidorgans Mature T cells(Medullarythymocytes) leavethethymusandmigrate to secondarylymphoidorgans

  24. 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 • https://www.youtube.com/watch?v=9E_UxnC_L2o

  25. 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

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

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

  28. ab CD4+ T cells Precursorsofhelper T cells (TH),THdifferentiate to severalsubtypes, whichsecretdifferentcytokines TH1- IL-2, IFNg; macrophagesactivation TH2- IL-4, IL-5, IL-6, IL-10; protectionagainstextracellularparasites TH17 - IL-17; proinflammatory, participationautoimmunediseases Tfh- (follicularhelper T cells); B cellsassistance Treg – (regulatory T cells) suppresstheactivityofothersT cells, especiallyautoreactive T cells; produce IL-10 andTGFbregulatory T cellsarise in thethymusfrom a part ofautoreactivelymphocytes

  29. ab CD8+ T cells Precursorsofcytotoxic T cells (TC) TC – recognizeanddestroycellsinfectedwithvirusesorthecellsinfectedwithotherintracellularparasitesandsomecancercells

  30. 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)

  31. T cell activation Signal:TCR– MHC gp I / II +Ag peptid (APC) Co-stimulatorysignal: CD 28 (T lymphocyte) – CD 80, CD 86 (APC) (Without costimulation the T cell becomes anergic ) Activation via TCR and CD28 results in proliferation and differentiation in effectoror memory cells https://www.youtube.com/watch?v=JPh9P1aEfMI

  32. Th1 and Th2 basedimmunereaction http://www.youtube.com/watch?v=iVMIZy-Y3f8

  33. TH1 basedimmunereaction • TH1 cell function is the defense against intracellular parasites • TH1 cells cooperate with macrophages and support the differentiation of cytotoxic T lymphocytes • Macrophages and dendritic cells stimulated by some micro-organisms produce IL-12 • A TH precursor that recognizes an infected macrophage and receives signals via TCR, CD28 and the IL-12 receptor proliferates and differentiates into effector TH1 cells • TH1 cells produce IFNg and IL-2

  34. TH1 basedimmunereaction • IFNgactivatesmacrophages (↑ antigen presentationandlysosomalactivity, activatesinducible NO synthase) • IL-2 isessentialfortheproliferationanddifferentiationof T lymphocytes • Activatedmacrophagesproducecytokines (IL-1, TNF ...) thatstimulateT cellsandstimulatelocalinflammation to suppressinfection • Interactionof TH1 cells and macrophagesis a fundamentalmechanismofdelayed-type hypersensitivity (DTH; hypersensitivity rection type IV)

  35. 29. Th2 based immune reaction

  36. Th2 based immune reaction • The basic function of TH2 cells is protection against extracellular parasites • TH2 cells cooperate with basophils, mast cells and eosinophils • TH2 cells helps B lymphocytes in IgE production • TH precursor, which recognize antigen on APC and receives signals via TCR, CD28, IL-4 receptor and IL-2 receptor proliferates and differentiates in effector TH2 • Th2 produces IL-4, IL-5, IL-6, IL-10

  37. Mutualregulationofactivities TH1versus TH2 • Whetherthe THprecursor cell willdevelopinto TH1 or TH2 decidescytokine ratio ofIL-12 and IL-4 • IL-12 isproduced by macrophagesanddendriticcellsstimulated by certainmicroorganisms • IL-4 isproduced 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

  38. Tfh – B cell assistance

  39. Tfh – B cell assistance • The Tfh cells promotes B cellmaturation, the help ismediated by cytokines (IL-21, IL-4…) and direct intracellular contact (CD40L) • The TH precursor, whichreceivesfrom APC signals through the TCR, CD 28and receives a signal from the B cell via the ICOS molecule, then differentiates in the Tfh cell • For stimulation of Bcells, there is usually a need for cooperation between APC → Tfh cell → B lymphocyte • In the case of the minimal model, it is sufficientcooperationbetweenTfh cell and B lymphocyte

  40. Tfh – B cell assistance Specific direct help for B cells: • The Tfh cellhelps to B cells stimulated with the same Ag • Tfh cell needsforthecytokinesecretionsignal via TCR(B cells must present the appropriate Ag peptide - HLA II that recognizes the TCR; signal via costimulatory CD28 receptor is no longer required) • Interaction between CD40 (B lymphocyte) and CD40L (Tfh cell) is essential for initiation of somatic mutations, isotypeswitching, and memory cells formation

  41. Tfh – B cell assistance

  42. 30. Tc based immune reaction

  43. Cytotoxic T cellsactivation • TCrecognizecellsinfectedwithvirusesorotherintracellularparasites, and some tumor cells • Professional APC are dendriticcellsormacrophagesthat are infectedwith virus, orphagocytedantigensfromdead, infected, tumor orstressedcells • In order APC couldactivatethe TCprecursor, APC mustbestimulated by contactwith TH1 cell via CD 40, thenthedendritic cell begins to express CD 80, CD86 and secretecytokines (IL-1, IL-12); IFNgincreaseexpressionof HLA molecul= changeofresting APC in activated

  44. Cytotoxic T cellsactivation • TC precursorwhichrecognizes a peptide-MHC gpIcomplexon thesurfaceof APC via TCR and receivessignals via CD 28 proliferates and differentiates to clonematureeffectorcytotoxiccells (CTL) • For full TC activationisnecessaryIL-12 and IL-2 • CTL are spread by bloodstreamintotissues; foractivationofcytotoxicmechanismsissufficientsignal via TCR

  45. CTL effectorfunctions • Cytotoxicgranulescontainingperforin,granzymesandgranulysin • Fas ligand (FasL)- whichbinds to theapoptotic receptor Fas (CD95) presented on thesurfaceof many differentcells (also on thesurfaceof TC) • TNFb • Activationofeffector mechanismus leads to apoptoticdeathofthetarget cell. • https://www.youtube.com/watch?v=WdCiaIS2LV4 • https://www.youtube.com/watch?v=iQoY4RprTxo

  46. CTL effectorfunctions • https://www.youtube.com/watch?v=Va1jaBGwoT8

  47. Physiologicalmechanismsofregulationoftheimmunesystem

  48. Regulation by antigen • Induce immune response and extinction • Affinity maturation of B lymphocytes • Maintaining immunological memory • Antigenic competition • Threshold density of the complexes HLA II- Ag on APC

  49. Regulation by antibodies • Antibodiescompetewiththe BCR for antigen (negative regulatorof B cell stimulation) • IgGimmunecomplexesbind to the BCR andFcR on B cells→blockingof B cell activation • Regulation via idiotypic network

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