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Chapter 3: Antigen Recognition by T lymphocytes TCR TH1 - T Helper cell type 1 TH2 - T Helper cell type 2 TC or TCL - cytotoxic T cell Mechanism of Self-tolerance Positive selection = bind to self Double selection = bind to strongly to self T-cell Receptor • Two Types 1) TCR and TCR T cells TCR and TCR T cells • Antigen Binding site - V and V • Similar to Fab fragment Functions and Properties of T Cells • T cells - Recognize MHC:peptide complex - Diverse Functions A) Stimulate other immune cells B) Cytotoxic - kill infected host cells - Cell:cell interactions • T cells - Dominant T-cell in epithelial tissue (only 1-5% in circulation) - Recognizes more than MHC:peptide - Not well characterized • Antigen-Recognition site = Peptide:MHC Recognition site • Single V region CDR1-3 for each chain • All TCRs on a single T cell are the same • Different T cells express different TCRs • Diversity mechanisms like BCRs Figure 3-3 No Ds in Vgene Occurs in the Thymus DJ first then VDJ in gene rearrangement Figure • -chain locus is within -chain locus 3-8 • Fewer V segments then and • Two D segments can be incorporated Functional T-cell Receptor Complex • Core complex • CD3 complex: , • (zeta) chain • Function of CD3 and : Transport Signal Transduction Invariant Chains Avidity Comparison of B and T cells PROPERTY B CELLS T CELLS Bone Marrow Thymus Pre-antigen Diversity YES YES Post antigen Diversity YES NO Single antigen specificity YES YES Variety Peptide:MHC Secreted form of Receptor Yes No Invariant signaling subunits Yes Yes Initial Development Antigen recognized Immunodeficiency diseases • SCID - severe combined immunodeficiency disease - Many causes but a rare disease - Classified according to lymphocyte profile (T B NK) - Bone Marrow transplant can cure • Omenn syndrome - RAG proteins have reduced activity - Patient is: T+ B- NK+ • CD3 and CD3 deficiency diseases - Mutations in some CD3 genes - Patient is: T+/TCR- B+ NK+ or T- B+ NK+ How do T cells recognize antigens? Antigen Processing Antigen Presentation Antigen Presenting Cell (APC) Professional APC MHC class I communicates with Tc cells MHC class II communicates with TH cells IR to Extracellular Pathogens (CD4-MHC II) 1. Antibodies needed 2. Pathogen recognition/internalization by professional APCs a. B cells b. Macrophages c. Dendritic cells 3. Phagolysosome degrades proteins to peptides 4. Peptides:MHC II complex transported to surface 5. Professional APC contacts CD4 T cells 6. CD4 TH cells secrete cytokines to signal B cell maturation IR to Intracellular Pathogens (CD8-MHC I) 1. Antibodies ineffective 2. Pathogen replicates in the cell and proteins are degraded in the cytoplasm of the cell 3. Peptides are transported into ER and bind MHC I and transported to the surface 4. MHC I expressing cells present to CD8 T cells 5. CD8 T cells (cytotoxic T cell, CTL) kills host cell Figure 3-11 Structures involved in MHC Presentation TCR CD4 and CD8 MHC1 and MHCII T cell Co-Receptors TH Binds MHC II TC Binds MHC I Figure 3-13 part 1 of 2 Variable Invariant CD8-MHC I CD8-3 CD4-MHC II CD4-2 Closed Open Figure 3-15 8-10 amino acids 13-25 amino acids Degenerate binding specificity Figure 3-16 Peptide Degradation and Transport Proteosome=Shredder Transporter associated with antigen processing Chaperones Calnexin Calreticulin Tapasin Bare lymphocyte syndrome -TAP deficiency -Viral infections Figure 3-19 Golgi Transport Acidic process Vacuolar Transport Prevention of Peptide:MHC II formation in ER CLIP - class II-associated invariant-chain peptide Invariant Chain (li) - Prevent peptide binding in ER - Deliver to vesicles HLA-DM - Release of CLIP, peptide loading TCR binds MHC and peptide Figure 3-21 part 2 of 3 CDR3 binds peptide CDR2 binds MHC CDR1a binds N-terminal CDR1b bind C-terminal • Cytokines can regulate expression • Interferon induces MHC II expression T-cell Diversity - Recombination - Structure of TCR and associated molecules - Immunodeficiency diseases Antigen Processing and Presentation - Intracellular vs Extracellular - MHC structure EXTRA Summary INTRA Li Proteasome MHC II TAP Golgi Vesicle MHC I Golgi Calnexin CLIP HLA-DM CD4 TH Calreticulin Tapasin CD8 TC Alleles: different forms of one gene Allotypes: different forms of one protein (isoforms) Polymorphic: alternative forms of one gene = Many alleles Oligomorphic: a few forms of one gene = Few alleles Monomorphic: no polymorphism Homozygous: same allele on both inherited chromosomes Heterozygous: different allele on both inherited chromosomes MHC in humans is called HLA (human leukocyte antigen complex) Figure 3-13 part 1 of 2 Variable Invariant No rearrangements or somatic changes Diversity is derived from 1) Gene families 2) Genetic polymorphism HLA-A,B,C -present peptide antigens to CD8 Tcells and interact with NK-cells HLA-E,G -interact with NK-cells HLA-F -? HLA-DP,DQ,DR - present peptide antigens to CD4 Tcells HLA-DM,DO -regulate peptide loading of DP,DQ,DR Human leukocyte antigen complex Abs used to ID MHC molecules react with leukocytes not RBCs Figure 3-24 part 1 of 2 Heavy Chain Heavy Chains Chromosome Organization of HLA complex Chr6 2-microglobulin on chr15 • and chain = GeneA and GeneB • Haplotype - combination of alleles inherited from Chr6 • 2% meiotic recombination rate generates population diversity •Crossover: Haplotypes, normally, are inherited intact and hence antigens encoded by different loci are inherited together (e.g., A2; B27; Cw2; DPw6; DQw9; DRw2). However, on occasions, there is crossing over between two parental chromosomes resulting in new recombinant haplotypes. Thus, any one specificity encoded by one locus may combine with specificities from other loci. This results in vast heterogeneity in the MHC make-up in a given population. • Cytokines (Interferons) coordinately regulate the group of genes - class I heavy chain and other associated genes • TAP transporter, Tapasin, Proteasome subunits - LMP2 and LMP7 ---> all proteins involved in Antigen Processing Interferon , , and ----> Class I , 2M, TAP, LMP2, LMP7 HLA II Interferon ----> CIITA transcription factor ---> genes, li chain MHC class II transactivator (CIITA) - deficiency leads to bare lymphocyte syndrome MHC I (single peptide binding chain ): 3 genes to present antigen HLA-A, HLA-B, HLA-C MHC II (two chains, and ): 3 genesb to present antigen HLA-DQ, HLA-DP, HLA-DR Each MHC II locus encodes a gene for the chain and a gene for the chain: e.g. HLA-DQA, HLA-DQB => MHC II isoforms HLA-DPA, HLA-DPB => MHC II isoforms HLA-DRA, HLA-DRB => MHC II isoforms Maternal: 3 MHC I genes HLA-AM, HLA-BM, HLA-CM Paternal: 3 MHC I genes HLA-AP, HLA-BP, HLA-CP 6 different MHC I proteins on all cells Heterozygous Maternal: 3 MHC II genes HLA-DPAM, HLA-DPBM HLA-DQAM, HLA-DQBM HLA-DRAM, HLA-DRBM Paternal: 3 MHC II genes HLA-DPAP, HLA-DPBP HLA-DQAP, HLA-DQBP HLA-DRAP, HLA-DRBP 6 different MHC II proteins on all cells (some individuals have 8 due to two HLA-DRB genes) Homozygous = one DR type Heterozygous = up to four DR combinations, but only 3 types can be made by one person HLA-DRAP, HLA-DRB1P HLA-DRAP, HLA-DRB3P HLA-DRAP, HLA-DRB4P Figure Correlation is mainly with HLA class I 3-34consistent with killing of virus infected cells Red – heterozygous for all the highly polymorphic HLA I & II Yellow - Homozygous for one locus Blue - Homozygous for two or three loci Seroconversion - when antibodies have first been detected Figure 3-28 part 1 of 2 MHC One MHC isoform can bind multiple peptides Contact residues - the MHC amino acid residues that interact with TCR or the bound peptide Figure 3-28 part 2 of 2 chain HLA-DR chain Error in the textbook on HLA-DR (oligomorphic vs invariant) Figure 3-29 Anchor residues (green) - peptide amino acids interacting with MHC Peptide binding motif - combination of anchor residues Figure 3-30 Co- MHC restriction - TCR recognizes the complex of both the peptide and MHC by interacting with exposed amino acid residues Balancing Selection Favors multiple alleles Large circles- totalFigure # antigenic peptides that can be presented via MHCI & MHCII small circles- total # antigenic peptides that can be presented via an individual MHCI & MHCII haplotype 3-31 Advantages for heterozygous for the MHC Figure 3-32 part 1 of 2 Figure 3-32 part 2 of 2 Different mechanism from recombination DNA is exchanged between alleles and copied in one direction to generation new MHC allele HLA B*5301Found in African populations and associated with resistance to severe malaria Figure 3-33 part 2 of 2 Recombination between alleles of a different gene Generation of new MHC alleles HLA B*4601- Found in southeast Asian populations and associated with susceptibility to nasopharyngeal carcinoma. MHC selection by Infectious Disease • Pathogens adapt to avoid MHC - recent MHC isoform may provide a survival advantage (hence higher frequency level) • Epidemic diseases place survival advantages on those who can best present pathogenic peptides • Only a minority of HLA alleles are common to all humans - most are recent and specific to ethnic groups HLA Type and Disease Susceptibility Ankylosing spondylitis IDDM Multiple Sclerosis Narcolepsy Rheumatoid arthritis Lupus (SLE) AIDS (rapid) AIDS (slow) B27 DR4/DR3 DR2 DR2 DR4 DR3 HLA-A29, HLA-B22 HLA-C16, HLA-DR11 HLA-B14, B27, B57 HLA-C8, C14 MHC polymorphism and Organ Transplants • Developing T cells that recognize complexes of peptide and MHC molecules on HEALTHY tissue (selfpeptides presented by self MHC) are DESTROYED • This results in the preservation of T cells that recognize non-self MHC (allogeneic MHC). These are alloreactive T cells and are 1-10% of total T-cell repertoire • Immune system is primed for rejection of foreign organs that express allogeneic MHC • THIS IS WHY YOU WANT TO MATCH HLA TYPE