T-cell receptor feature. Antibody/antigen interaction. Major Histocompatibility Complex. Antigen processing. Antigen presentation

Transcription

1 ntibody/antigen interaction Major Histocompatibility Complex ntigen processing ntigen presentation PC/T-cell interaction T-cell receptor feature CD4+ T-Cell HL/peptide/TCR complex CD8+ T-Cell Proteasome Ribosomes Pathogens Exogenous particles etc HL-class II PC HL-class I TCR 1

2 peptide MHC/peptide complex The Major Histocompatibility Complex (Human Leukocyte ntigen, in Human) cell membrane MHC molecule The Key to How T Cells See the Universe Part 1 The Major Histocompatibility Complex 2

3 The discovery gglutination of the leucocytes of twins with the aid of leuco-agglutination sera Monozygotic twins Leuco-agglutination sera u Ch Ce Le Bo Te Ro De Ds Rb Vc Ba Pu Lx P.Va J.Va E.Ro H.Ro D.Te B.Te Dizygotic twins L.Go V.Ro Dausset and Brecy, Nature, : 1430 The discovery (2) Leuco-agglutination sera formed after blood transfusion Monospecific leuco-agglutination antibodies formed during pregnancy Family studies showing Mendelian segregation Importance in trasplantation and tests of the human transplant failures Development of microtoxicity tests (Terasaky) Computer facility for analysing multiple 2x2 χ 2 tables Development of the Mixed Lymphocyte Reaction tests Studies on cousin marriage families (identified thanks to the Roman Catholic church archives) Identification of the cross-over between the different Leukocytes groups identified Idea that it was one genetic system and not different groups (like blood groups) 10 WORKSHOPS in less than 30 years!!! No patent requests and full sharing of reagents betwen groups and setting of a repository The discovery (3) The molecular genetic of HL Detailed Map of HL region Chromosome 6 HL complex 0 Kb 6p21.3 Class I Class III Class II 4000 Kb 3

4 HL (genetic products) Class I MHC heavy (α) chain genes: HL-, HL-B & HL-C HL Class I MHC region HL CLSS I 4

5 CD8 T cell MHC I Cytoplasm ECH LOCUS ENCODES EITHER N LPH CHIN GENE OR BET CHIN GENE Nucleated cell HL Class II MHC region HL CLSS II 5

6 CD4 Differential distribution of MHC molecules T cell MHC II ntigen presenting cell Intravesicular Extracellular Tissue MHC class I MHC class II T cells +++ +/- B cells Macrophages Other PC Epithelial cells of thymus Neutrophils Hepatocytes + - Kidney + - Brain + - Erythrocytes - - WHT TYPES OF GENES RE ENCODED BY THE MHC? The MHC basically contains 3 types of genes: Type of gene MHC region Function Class I MHC Class I region Peptide presentation to CD8 T cells Class II MHC Class II region Peptide presentation to CD4 T cells Class III MHC Class III region Multiple: do not involve antigen presentation examples: genes for C4, C3, factor B (Bf) 6

7 HL characteristics HL (genetic products) - Polygenic: many genes: - HL-, -B, -C; HL-DR, -DP, -DQ HL characteristics - Polygenic: many genes: - HL-, -B, -C; HL-DR, -DP, -DQ - Codominance: - both paternal and maternal genes are expressed Diversity of MHC molecules in the individual HPLOTYPE 1 HPLOTYPE 2 DP DQ DR β α β α β1 α DP DQ DR β α β α β1 α DP DQ DR β α β α β1 α B C B C B C Polygeny Variant alleles polymorphism dditional set of variant alleles on second chromosome MHC molecules are CODOMINNTLY expressed Two of each of the six types of MHC molecule are expressed Genes in the MHC are tightly LINKED and usually inherited in a group The combination of alleles on a chromosome is an MHC HPLOTYPE 7

8 HL characteristics. HL- D. HL-DP - Polygenic: many genes: - HL-, -B, -C; HL-DR, -DP, -DQ - Codominance: - both paternal and maternal genes are expressed B. HL-B E. HL-DQ - Polyallelic: many gene alleles at each locus (e.g., HL-B) - HL-B8, HL-B15, HL-B27 - Polymorphic: the HL molecules are highly polymorphic (variations in primary amino acid sequence) as a consequence of polyallelism C. HL-C F. HL-DRB1 Number of HL alleles in the HL/IMGT database Class I B C E F G H J K L Class II DR DRB DQ1 DQB1 DP1 DPB1 DM DMB DO DOB HL-DR DRB1 DRB2 DRB3 DRB4 DRB5 DRB6 DRB7 DRB8 DRB9 TOT Other non-hl genes MIC MICB MICC MICD MICE TP1 TP2 LMP2 LMP pril 2003 update Nomenclature for factors of HL alleles Nomenclature Indicates HL the HL region and prefix for an HL gene HL-DRB1 a particular HL locus, i.e. DRB1 HL-DRB1*13 a group of alleles encoding the DR13 specificity HL-DRB1*1301 a specific HL allele HL-DRB1*1301N a null allele HL-DRB1* an allele which differ by a synonymous mutation HL-DRB1* an allele which contaning a mutation outside the coding region HL-DRB1* N a null allele contaning a mutation outside the coding region HL-DRB1* L an allele contaning a mutation outside the coding region which leads to a lower level of expression By default: HL-DRB1*

9 How diverse are HL molecules in the population? IF each individual had 6 types of MHC the alleles of each MHC type were randomly distributed in the population any of the about 2000 alleles could be present with any other allele ~2 x unique combinations x x x x In reality MHC alleles are NOT randomly distributed in the population lleles segregate with lineage and race Group of alleles HL-1 HL- 2 HL- 3 HL- 28 HL- 36 Frequency (%) CU FR SI Secondary Hot-spots of recombination Primary Hot-spots of recombination Inheritance of MHC haplotypes DP-1,2 DQ-3,4 DR-5,6 B-7,8 C-9,10-11,12 DP-9,8 DQ-7,6 DR-5,4 B-3,2 C-1,8-9,10 Parents DP DQ DR DP DQ DR X DP DQ DR DP DQ DR BC BC BC BC Children DP-1,9 DQ-3,7 DR-5,5 B-7,3 C-9,1-11,9 DP-1,8 DQ-3,6 DR-5,4 B-7,2 C-9,8-11,10 DP-2,8 DQ-4,6 DR-6,4 B-8,2 C-10,8-12,10 DP-2,9 DQ-4,7 DR-6,5 B-8,3 C-10,10-12,9 DP DQ DR BC DP DQ DR BC DP DQ DR BC DP DQ DR BC DP DQ DR BC DP DQ DR BC DP DQ DR BC DP DQ DR BC Haplotype HL identical (share both haplotypes) 9

10 Haplotype Haplotype HL haploidentical ( half -identical; share one haplotype) HL nonidentical no shared haplotypes) RIBBON DIGRM: Which is the functional role of the polymorphisms of HL molecules? PEPTIDE WITHIN THE GROOVE FOR CLSS I MHC SPCE-FILLING DIGRM: PEPTIDE WITHIN THE GROOVE FOR CLSS I MHC 10

11 Class I MHC Class I MHC Interaction between HL class I and peptide Pocket B Pocket F Class I MHC HL classe I 11

12 Interaction between HL class I and peptide RIBBON DIGRM: PEPTIDE HNGS OUT OF THE GROOVE (CLSS II MHC) SPCE-FILLING DIGRM: PEPTIDE HNGS OUT OF THE GROOVE (CLSS II MHC) Class II MHC Class II MHC 12

13 Interaction between HL class II and peptide P1 P4 P6 P9 Class II MHC HL classe II Interaction between HL class II and peptide HL polymorphisms (1) HL-DP2(E69) -0.7 P1 P4 P6 P B. HL-DP2K69 HL classe II -0.7 Berretta et al

14 HL polymorphisms (2) Non-self HL-DP2 P4 affinities HL-DP2k69 P4 affinities V S T P L I D (W T) Y W R Q N M K H G F E C V T S G C Y W R Q P N M L K I H F E D (W T) Individual peptides derived from a pathogen IC 50 µ M IC 50 µ M Position P4 of HL-DP2 preferentially bind polar, aromatic or positive charged residues. Posizione P4 of HL-DP2k69 bind preferentially only aromatic residues. Berretta et al Simplistic model for HL molecules encoded by a single chr.: 1 st set of 3 ellipses: potential epitopes presented to CD8 T cells 2 nd set of 4 ellipses: potential epitopes presented to CD4 T cells Being polygenic & polyallelic: : many peptides can be presented to CD4 T cells and CD8 T cells For the human population: ~all peptides can be presented to CD4 T cells and CD8 T cells Non-self Part 2 ntigen processing Potential presentation of any pathogen that contains peptides or proteins! 14

15 ntigen processing for extracellular antigens (1) CD4+ T-Cell HL/peptide/TCR complex CD8+ T-Cell Proteasome Ribosomes Pathogens Exogenous particles etc HL-class II PC HL-class I TCR ntigen processing for extracellular antigens (2) Figure 5-7 part 2 of 2 ntigen processing for extracellular antigens (3) Figure

16 ntigen processing for intracellular antigens (1) ntigen processing for intracellular antigens (2) HL/peptide/TCR complex CD8+ T-Cell Proteasome Ribosomes PC TCR HL-class I ntigen processing for intracellular antigens (3) Figure 5-6 Figure

17 Figure 5-17 Part 3 ntigen presentation Figure 8-10 Figure

18 Figure 8-8 Figure 8-12 Figure 8-16 part 2 of 2 Figure

19 Risposta Cellulo-mediata Quali segnali sono necessari per attivare i linfociti T, quali recettori sono utilizzati per cogliere tali segnali e rispondere ad essi Come si espandono i pochi linfociti T vergini specifici per un dato antigene per dare origine a una popolazione di linfociti T effettori in grado di eliminare i microbi Quali molecole prodotte dai linfociti T mediano la comunicazione con altre cellule come macrofagi e linfociti B 1

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