1.  The most important mediators of indirect cell communication in the immune system („hormones” of the immune system).  Act in low concentrations. Cytokines can affect in an autocrine way, in a paracrine way, or in an endocrine way  pleiotropic effect.  Cytokines can act by synergistic or antagonistic ways to each other. A given cell may by affected by many cytokines resulting in the same effect  redundant effect. -The responsiveness of the given cell is based on the expression of cytokine-specific receptors. THE MOST IMPORTANT FEATURES OF CYTOKINES !

2. Recognition is inevitable Innate immunity as a first line of defence Innate immune cells recognize frequently found structures of pathogens, these are not found in human cells! Examples: duple strain RNA bacterial cell wall components bacterial flagellin…. !!

3. Danger signal! The innate immune system also recognizes molecules that are released from damaged or necrotic cells. Such molecules are called damage-associated molecular patterns (DAMPs). !!

4. direct connetion between innate cells and pathogen )( Specificity of innate immunity Few receptors (20-30) are responsible for the recognition of all the pathogens !

5. INNATE IMMUNITY II Effector functions, elimination of pathogens 1.Phagocytosis 2.Killing with soluble mediators 3.Complement system 4.NK cell activation !!

6. Monocite / macrofage DC Mast cell Granulo- cites NK cell B cell T cell Comple- ment Recogni -tion PRR Absen- ce of MHCI Cell-cel (APC) Communi cation Soluble effector function Phagocyto sis Killing with solubl e mediat ors Phagocy tosis Killing with solu ble medi ators Pathogen and cell killing Pathogen Killing

7. Monocita/ makrofág DCHízó Sejt Granu locita NK sejtB-sejtT-sejtKomp lement Felis merés kommu nikáció APC Effektor funkció

8. T helper cells (T H cells) assist other white blood cells in immunologic processes Cytotoxic T cells (T C cells, or CTLs) destroy virally infected cells and tumor cells ! !

9. Proteins are composed primarily of polypeptides (and often non-polypeptide cofactors. ) Peptides are short chains of amino acid monomers linked by peptide (amide) bonds.

10. ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES II T No T-cell response soluble Ag Native membrane Ag Peptide antigen Cell surface MHC- peptide complex T-cell response Cell surface peptides APC ! !

11. Dendritic cells take up antigen in the tissues, migrate to peripheral lymphoid organs, and present foreign antigens to naive T cells.

14. How can detect the immune system the intracellular pathogens? PRR Antigen presentation Display intracellular peptides on the surface of cells

15. MHC Major histocompatibility comlex cell surface molecules mediate interactions of T cells with antigen presenting cells

16. PEPTIDE 11 33 22 2m2m STRUCTURE OF CLASS I MHC MOLECULES MHCI Expressed by all nucleated cells ! !

17. 22 11 22 11 PEPTIDE STRUCTURE OF CLASS II MHC MOLECULES MHCII Expressed by professional antigen presenting cells Macrophage, dendritic cell, B cell ! !

18. MEMBRANE RECEPTORS Intracellular peptide binding capacity One binding site can accomodate multiple peptides

19. MHC class I accommodate peptides of 8-10 amino acids Cleft geometry MHC class II accommodate peptides of >13 amino acids  -M  -chain Peptide  -chain  -chain Peptide

21. CYTOSOL-DERIVED PEPTIDES ARE PRESENTED BY MHC-I FOR T-CELLS

22. Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules presented to cytotoxic T cells Tc Endogenous Ag RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES Exogenous Ag Th Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper T cells TCR Peptide MHCI TCR Peptide MHCII APC ! !

23. MHC RESTRICTION One single T-cell receptor can recognize a given MHC – peptid complex The TCR-specific peptide is recognized only when its presented with an MHC on which the TCR had been selected during its development in the thymus If the peptide binds to another MHC molecule no T-cell recognition occurs (by this T cell) If the same MHC molecule binds another peptide, no T-cell recognition occurs !

24. ! ! T cell receptor (TCR) recognizes peptide antigen and simultaneously also recognizes the MHC molecule that is displaying that peptide

25. Specificity of innate immunity Specificity of T cells Tc APC Tc APC peptid MHC Peptides derived from different microbes Distinct T cell receptors !

26. direct connetion between innate cells and pathogen No direct connetion between T cell and pathogen APC-T cell connection APC T peptid MHC T Peptides derived from different microbes Distinct T cell receptors )( Specificity of innate immunity Specificity of T cells !

27. A given type of MHC is able to bind different peptides Does not distinguish self and nonself peptides !

28. B cell epitopT cell epitop B cells recognize: proteins polysaccharides lipids DNS steroids drugs, etc Tissue or soluble antigens T cells recognize: peptides (8-23 amino acid) only when these peptides are presented by MHC molecules on APC cells ! !

29. MHCI Displays intracellular antigens to cytotoxic T cells ! !

30. ER is the site of protein synthesis

31. MHC molecules are also synthetised in ER

32. Degradation of endogenous proteins takes place in the proteasomes, they are presented on MHC I

33. ER membrane Lumen of ER Cytosol Transporters associated with antigen processing (TAP1 & 2) Transporter has preference for longer than 8 amino acid peptides with hydrophobic C termini. TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide ER membrane Lumen of ER Cytosol TAP-1 TAP-2 Peptide ATP-binding cassette (ABC) domain Hydrophobic transmembrane domain Peptide antigens from proteasome

34. Degradation of endogenous proteins in (immune) proteasomes TAP: Transporter associated with antigen processing

36. MHCII Displays extracellular antigens to helper T cells ! !

37. Professional phagocytic cells macrophages neutrophyl granulocytes dendrtitic cells the phagocytosed cells or molecules may modify the functions of the cell phagocytosis followed by enzymatic degradation Professional antigen presenting cells macrophages B lymphocytes dendrtitic cells they express MHCII molecules the protein degradation products (peptides) can be presented to T lymphocytes by MHC molecules ! ! ! !

38. 1 Recognition 2. Uptake 3. Peptide production 4. MHCII-peptide complex 5. Presentation

39. Pathogen recognition by innate immune system 1.Directly via PRR 2.Indirectly via opsonization 1 Recognition

40. Phagocytosis 2. Uptake

41. 3. Peptide production

42. !

44. Invariant chain (Ii) function: 1.Chaperon – Conformation 2.Blocking of the peptide binding 3.Transport of MHC complex

45. Comparision of intracellular events of MHCI and MHCII pathways

47. T cell recognition Peptide fragments Peptides associate to MHC Expression of peptide/MHC complex on the cell surface Recognition of peptide/MHC complex by TCR Antigen prezenting cell T cell

49. Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules presented to cytotoxic T cells Tc Endogenous Ag RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES Exogenous Ag Th Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper T cells TCR Peptide MHCI TCR Peptide MHCII APC ! !