Presentation is loading. Please wait.

Presentation is loading. Please wait.

ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES Y T No T-cell response soluble Ag Native.

Similar presentations


Presentation on theme: "ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES Y T No T-cell response soluble Ag Native."— Presentation transcript:

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

2 REQUIREMENTS FOR ANTIGEN PRESENTATION 1.Expression of MHC molecules 2.ANTIGEN a) Synthesis of viral antigens - intracellular b) Uptake of protein antigens – extracellular 3. „Processing” of antigen generation of peptides suitable for T-cell recognition 4. Presentation of peptides in complex with MHC molecules on the cell surface T-cells with  TCR are specialized for recognizing protein – derived fragments

3 THE STRUCTURE OF MHC

4 MEMBERS OF THE IMMUNOGLOBULIN SUPERGENE FAMILY FUNCTION RECOGNITION Ig, TCR, MHC-I, MHC-II ADHESION ICAM-1, ICAM-2, VCAM-1, NCAM BINDING CD4, CD8, CD28, B7, IL-1RI, PDGFR, Fc  RII, poly-IgR MOLECULES CONTAINING ONE OR MORE Ig DOMAIN(S) V or C domain related

5 There are two types of MHC molecule, MHC class I and MHC class II.

6 CELL SURFACE EXPRESSION OF MHC ON VARIOUS CELL TYPES Szövet MHC I MHC II T cells+++ +/- B cells Makrophages Dendritic cells Epithelial cells Neutrophyls+++ - Hepatocytes + - Kidney + - Brain + - Eritrocytes -- Cell surface expression of MHC is influenced by activation MHC class I molecules are important in immune responses agains viruses and tumour cells MHC class II plays a role in the activation of immunocytes and in the regulation of cell cell cooperation

7 Genes and proteins of MHC

8 Some members of the immunoglobulin supergene family FUNKCTION RECOGNITION Ig, TCR, MHC-I, MHC-II ADHESION ICAM-1, ICAM-2, VCAM-1, NCAM BINDING CD4, CD8, CD28, B7, IL-1RI, PDGFR, Fc  RII, poly-IgR EGY VAGY TÖBB Ig DOMÉNT TARTALMAZÓ FEHÉRJÉK V vagy C doménhez hasonló

9 MHC class I and MHC class II molecules bind to different T-cell co-receptors.

10 The structure of MHC proteins

11 THE PEPTIDE BINDING SITE OF MHC CLASS I MOLECULES

12 THE PEPTIDE BINDING SITE OF MHC CLASS II MOLECULES PEPTIDE

13 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

14 How can 6 invariant molecules have the capacity to bind to 1,000,000,000,000,000 different peptides? The number of different T cell antigen receptors is estimated to be 1,000,000,000,000,000 (10 15 )

15 Peptides can be eluted from MHC molecules Acid elute peptides

16 Eluted peptides from MHC molecules have different sequences but contain motifs Peptides bound to a particular type of MHC class I molecule have conserved patterns of amino acids PEIYSFH I AVTYKQT L PSAYSIK I RTRYTQLV NC Tethering amino acids need not be identical but must be related Y & F are aromatic V, L & I are hydrophobic Side chains of anchor residues bind into POCKETS in the MHC molecule SIIFNEKL APGYNPAL RGYYVQQL Different types of MHC molecule bind peptides with different patterns of conserved amino acids A common sequence in a peptide antigen that binds to an MHC molecule is called a MOTIF Amino acids common to many peptides tether the peptide to structural features of the MHC molecule ANCHOR RESIDUES

17

18 A flexible binding site? A binding site that is flexible at an early, intracellular stage of maturation Formed by folding the MHC molecules around the peptide. FloppyCompact Allows a single type of MHC molecule to bind many different peptides bind peptides with high affinity form stable complexes at the cell surface Export only molecules that have captured a peptide to the cell surface Venus fly trap

19 MHC molecules bind peptides according to the following principals Use a small number of anchor residues to tether the peptide- this allows different sequences between anchors and different lengths of peptide Adopt a flexible “floppy” conformation until a peptide binds Fold around the peptide to increase stability of the complex

20 MECHANISM OF ANTIGEN PRESENTATION

21 Endogenous peptides are presented on MHC I (vírus proteins, tumor antigens) Tc Endogenous Ag THE ENDOGENOUS AND EXOGENOUS ROUTES OF ANTIGEN PRESENTATION Exogenous Ag Th Exogenous peptides (toxins, bacterium, allergen) are presented by MHC II

22 The MHC I receptor binds the CD8 receptor, while MHC II binds CD4.

23 11 33 22 2m2m 22 11 22 11 Allelic polymorphism is concentrated in the peptide antigen binding site Polymorphism in the MHC affects peptide antigen binding Allelic variants may differ by 20 amino acids Class II (HLA-DR) Class I

24 Cytosol-derived peptides are presented by MHCI receptors

25 Degradation of endogenous proteins in the (immun)proteosomes TAP: Transporter associated With antigen processing

26 Multiple proteins help Ag presentation of MHCI

27 Trimming of antigenic peptides by ERAP

28 Presentation of extracellular (Exogen) peptides bemutatása (MHCII prezentáció)

29 Invariant chain protects the binding site of MHCII until it reaches the appropriate compartment INVARIÁNS LÁNC (Ii) 1.Chaperon – konformáció 2.Peptidkötőhely gátlása 3.Szállító/visszatartó molekula DMA/DMB 1. A peptidet befogadó konformáció fenntartása 2. A CLIP és az exogén fehérjékből származó peptidek lecserélése

30 The biological function of MHC proteins

31 AZ MHC FUNCTIONS –Presentation of peptides– self/altered self/foeign peptides –Continous expression of self-peptidesto monitor cellular health –Determination of immunological self Self MHC + self peptide – individual MHC pluss és saját peptid Allogeneic response to fotreign MHC (transplantation) Self MHC– autolgous foreign MHC allogeneic activation. Az The ratio of alloreactive T-cells is very high: 1-10% –A differentiation and selection of developing thymocytes (in the thymus) –promotion of T-limphocyte survival in the priphery week” tonic” signals induced by MHC / TCR interactions provide survival signals –Inhibitory ligands for NK cells, maintainance of host cell integrity.

32 AZ MHC restriction TCR/ MHC + peptid complex recognized A single TCR recognize a single MHC-peptid komplex The same peptide presented on a different MHC is not recognized. The same MHC molecule with a different peptide is not recognized by a given TCR (other TCRs may recognize)

33 © Media Graphics International MICE Y Virus A T - CELLS T T T T T T Vírus B Vírus B + Y sejtek T Vírus A + Y sejtek T MICE X Vírus A + X cells T Virus A + X cells T T Experiment of Peter DOHERTY & Rolph ZINKERNAGEL 1976 Cells infected with a virus are only killed if the infected cell and virus-specific T cells are from the same animal or strain. (The MHC needs to be recognized by the CTL cells MHC restriction ).

34 Mice X Thymec tomy No T cells MiceY MiceX Tissue compatibility is encoded by the MHC genes and tissue rejection requires the presence of T cells No rejection

35 The MHC locus MHC protein (HLA)- coding genes

36 3,838,986 bp 224 gene 6 kromoszóma MHC sequencing consortium Nature 401, 1999 The full sequence and the map of the human MHC locus HUMAN GENOME PROJECT

37 Klasszikus MHC gének POLIMORPHIC HLA – Human Leukocyte Antigen system HLA –A,B, C I osztály ALL NUCLEATED CELLLS HLA – DR, DP, DQClass II ON PROFESSIONAL APC Non- classical MHC genes E, G, F 6 kromoszóma rövid karjaMHC 15 kromoszóma  2m STRUCTURE OF THE MHC Class III

38

39 INHERITENCE OF CLASS I AND CLASS II MHC GENES HUMAN LEUKOCYTE ANTIGEN HLA EVERY CELL α1β1α1β1α2β2α2β2 PROFESSIONAL APC I osztály II osztály Ko-domináns öröklésmenet

40

41 In reality allels are not inherited randomy. Allels are linked, and there must have been strong selection favoring certain allelic variants. Non- random distribution CAU AFR ASI Frequency (%) HLA-A1 HLA- A2 HLA- A3 HLA- A28 HLA- A36 Allels ABC A polimorfizmus (allélek) száma CLASS I 1652 allels   CLASS II 688 allels 872 DRDPDQ ~6 x combinations POLIMORPHYSM OF MHC IN HUMAN POPULATIONS

42 Classical MHC genes are inherited as haplotypes BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR X Parents DP-1,2 DQ-3,4 DR-5,6 B-7,8 C-9,10 A-11,12 DP-9,8 DQ-7,6 DR-5,4 B-3,2 C-1,8 A-9,10 DP-1,8 DQ-3,6 DR-5,4 B-7,2 C-9,8 A-11,10 DP-1,9 DQ-3,7 DR-5,5 B-7,3 C-9,1 A-11,9 DP-2,8 DQ-4,6 DR-6,4 B-8,2 C-10,8 A-12,10 DP-2,9 DQ-4,7 DR-6,5 B-8,3 C-10,10 A-12,9 BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR Offspring

43 MHC MOLECULES ARE EXPRESSED WITH BOUND PEPTIDES DERIVED FROM SELF OR NON-SELF PROTEINS B-cell, macrophage, dendritic cell Kidney epithelial cell Liver cell Present intracellular environment Present intra- and extracellular environment Class I MHC Peptides of restricted size, which derive from cytosolic or nuclear proteins Class II MHC Overlapping peptides of various sizes, which derive from membrane proteins 70% derives from MHC molecules

44 MHC Polimorphysm is maintained by the presence of pathogens

45 THE OUTCOME OF INFECTION IN A POPULATION WITH POLYMORPHIC MHC GENESMHC-Gen v v v v v v v v v v v v v vvv v v v v v v v v v Example: If MHC X was the only type of MHC molecule Population threatened with extinction V – virus infection Pathogen that evades MHC X MHC XX Population is protected


Download ppt "ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES Y T No T-cell response soluble Ag Native."

Similar presentations


Ads by Google