New Immunology Chapter 5 PDF

Chapter 5 tigen Recognition by T Lymphocy Objectives Describe T cell receptor structure and understand how diversity is generated by somatic recombination in T cell receptors Explain how TCR structure and diversity compares to that of immunoglobulin receptors in B cells Desc...

Chapter 5 tigen Recognition by T Lymphocy Objectives Describe T cell receptor structure and understand how diversity is generated by somatic recombination in T cell receptors Explain how TCR structure and diversity compares to that of immunoglobulin receptors in B cells Describe antigen processing and presentation by both the class I MHC and class II MHC pathways, and explain how these pathways are critical for activation of CD8 and CD4 T cells Describe structural features of MHC molecules and the genes that encode them Explain what contributes to diversity in MHC molecules within an individual and how this diversity impacts a population as a whole Understand the benefits of MHC heterozygosity Describe the role of MHC molecules in rejection of transplanted  Comparison : Ab to TCR similarities differences both have 2 chains, Antigens : each - Ab : wide range with 1 variable region and (CHO’s, proteins, lipids) 1 constant region - TCR : peptides/MHC only No further change in TCR gene rearrangement after Ag stimulation (no SHM (somatic or CSR) recombination) produces sequence binding sites for antigen: variability in both - Ab : 2 or more - TCR : 1 TCR is membrane bound TCR resembles Fab of antibody Complementarity determining regions : most variable regions of antigen binding site Ig-like domains TCR : cell surface only each T cell has a unique TCR TCR diversity: somatic recombination only 1 Ca gene segment VJ rearrangement, junctional diversity (P,N nucleotide inser VDJ rearrangement, junctional diversity (P,N nucleotide inser  RAG Proteins are essential for adaptive immunity Omenn syndrome -partial loss of RAG protein activity, SCID (severe combined still fatal immunodeficiency) - absence of RAG proteins - no B or T cells, no adaptive immunity, fatal Rash from chronic inflammation Candida albicans infection in mouth treatment for both : bone marrow transplant at birt  TCR Complex In ER, TCR a,b associate with CD3g CD3d 2x CD3e 2x z  needed to 1) transport TCR to bind signalin molecules surface 2) transduce signals electrostatic interactions A small subset of T cells have g,d TCR 1-5% of T cells function less defined can bind peptide without MH  g,d TCR gene rearrangement d chain : more junctional diversity than b chain d chain locus is between V, J of a chain locus TCR : more diversity than Ig in somatic recombination essing and Presentation of Patho Antigen role of MHC molecules  Antigen Presenting Cells process antigen and present it on MHC to T cells igen processing : degrading of pathogen-derived proteins into peptide igen presentation : binding of peptide by MHC and display at cell surfa  2 different MHC molecules present processed antigen to T cells MHC class I: MHC class II: Presents peptide Presents peptide from intracellular from extracellular pathogen pathogen (e.g., virus) (e.g., bacterium) peptid e a3, b2 microglobulin: a2, b2 : g-like domains Ig-like domains  2 types of T cells are distinguished by coreceptor/MHC interaction cytotoxic T cells: bind helper T cells: bind  Differential MHC Expression activated T cells only **professional APCs class I MHC : on increases in MHC levels almost every cell can be induced by IFN-g during immune respons HIV binds CD4 on T cells http://www.bio8.info/2011/08/human-immunodeficiency-virus- hiv.html T cells : 2 different effector functions 1. kill infected 2. help other cell cell ↑ microbicidal activity B cell differentiation  MHC I,II bind peptides in different compartments MHC I (intracellular cytosol - site of protein MHC II synthesis (for host extracellular): cell and internal esicular system pathogen) continuous with  MHC I binds extracellular peptide from fluid intracellular  MHC II binds pathogen peptide from extracellular pathogen  MHC molecules bind peptides MHC is promiscuous : ach one an bind many ifferent eptides peptide : 8-10 aa 13-25 aa ends bind ends do not bind pockets pockets; bind along in MHC entire length hydrophobic or  longer, more basic aa at varied lengths  TCR : MHC Interaction plane of b CDR1,2 TCR a,b CDR3 (most variable) a CDR1,2 peptide : dark yellow TCR plane of TCR CDR3s of TCR contact sid chain of 1 residue of aa in middle of peptide CDR1 and 2 contact MHC molecule tigen processing and presentatio MHC class I pathway intracellular pathogen  MHC I: Proteasome degrades cytoplasmic proteins into peptides to present to CD8 T cells proteasome normally degrades misfolded, damaged, or unneeded proteins during viral infection, IFN-g (from NK cells) causes changes in infected cell’s proteasome: favors production of peptides for class I MHC - immunoproteasome: modified subunits + cap proteins  makes peptides with hydrophobic or basic carboxy terminus, facilitating binding to MHC I MHC I: Transport of antigenic peptides 1. cytosol  ER TAP : Transporter Associated with antigen Processing bare lymphocyte syndrom TAP nonfunctional, no peptides enter ER  very few MHC I on surface  immunodeficient  antigenic peptides 2. assembly and loading in ER peptide binding completes folding Golgi (chaperone) PM (chaperone) tide loading complex : stabilizes MHC heavy chain + b2 microglobulin  positions it to receive peptides tigen processing and presentatio MHC class II pathway extracellular pathogen MHC II: external pathogen peptide is generated in endocytic vesicle phagosome fuses with lysosome vesicle carrying MHC II in outward secretory  low pH activates proteases to degrade pathogen proteins into peptides pathway fuses with phagolysosome MHC II binds peptide MHC II/peptide is delivered to PM  MHC class I and II antigen presentation MHC class MHC class II pathway I pathway samples samples external internal environme environme nt nt Even without infection, MHC I and II are constantly presentin self-peptides that should not be recognized by TCR  Antigen presentation on MHC is needed for 2 stages of T cell function is primed by dendritic cell: T cell activation occurs in secondary lymphoid tissue the nature of T cell these interactions dendritic cell depends on the type of pathogen performs effector cell function: T cell modifies anoth occurs at infection site, secondary lymphoid tissue, pe  CTL Response (MHC I) (intracellular pathogens : viruses, some bacteria) 2. Dendritic cell 1. Virus infects dendritic CD8 migrates to cell at lymph node and infection site: activates naive CTL there (“priming step”) CTL: naïve effector CTL recognizes same peptide presented by dendritic cell in lymph node and by other infected cell at infected site 3. effector CTL migrat Inside infected cell at to infection site and k infection site: infected cell there  Helper (MHC II) Response : MØ tracellular pathogens activation : bacteria, some viruses, parasites, fu 1. Dendritic cell phagocytoses 2. Dendritic cell migrates pathogen CD4 to lymph at infection site: node and activates naive helper T cell there (“priming step”) helper T cell: naive  effector Helper T cell recognizes same peptide presented by dendritic cell in lymph node and by macrophage at infection site Inside MØ at infection site : 3. effector helper T cell migrates to infection site and  Helper (MHC II) Response : B cell xtracellular pathogens activation : bacteria, some viruses, parasites, fu 1. Dendritic cell phagocytoses 2. Dendritic cell migrates pathogen at CD4 to lymph infection site: node and activates naïve helper T cell there (“priming step”) helper T cell: naïve  effector Helper T cells recongizes same peptide presented by dendritic cell in lymph node and by B cell in lymph node Inside B cell in lymph 3. effector helper T cell node: helps B cell in lymph no  Cross Presentation: MHC I Response via Endocytic Pathway C is not infected with virus, cytotoxic response can still be m ple : hepatitis C virus only infects liver cells, not dendritic cells, but a CD ponse against the virus is still generated! es virus via class II path then presents peptide:MHC I to CTL via class I cal in dendritic cells because only they can initiate primary T cel how this occurs is unclear possibilities : (2) 1) in APC, peptide complexes from (2) infected, (1) dead phagocytosed microbe are (1) transferred to MHC I in intracellular vesicles  then peptide:MHC I goes to cell (1) surface or e arrows: normal class I pathway 2) in APC, viral parts are delivered red arrows: cross presentation  Evasion of peptide presentation by mycobacteria Pieters , Microbes and Infection Volume 3, Issue 3, March 2001, Pages 249–255 oval of TACO protein coat on endocytic vesicles allows acidifi d degradation of contents in lysosome hogens can prevent removal of TACO coat prevents degradation and presentation of peptides on urces of diversity in MHC molecu  MHC : inherited diversity human MHC : human leukocyte antigen (HLA) complex (expressed on white blood cells) there is huge diversity in MHC in a population – very different MHC molecules are usually expressed on APCs from different people 2 sources of this diversity: i. different gene families : each person has multiple genes for MHC Ia chain (HLA A,B,C) and MHC IIa and b chains (HLA DPA and DPB, DQA and DQB, DRA MHC andgene cluster on human chromosome 6 : DRB)  isotypes : different proteins in a gene family ii. genetic polymorphisms : multiple forms of these genes in one person vs. another  MHC : inherited. MHC Isotypes: diversity * resent peptides to CD8 T cells ** present peptide to CD4 T cells orphism in MHC alleles is uniquely large ! (non-MHC) oligomorphic alleles differ from each other in 1 (or at most a few) am alleles can differ from each other in 56 amino acids ! ifferences are mostly in peptide binding groove Tak and Saunders, The Immune Response : Basic and Clinical Prinnciples  MHC : inherited. MHC Allotypes: igh polymorphism: diversity Number of housands of allotypes: fferent MHC number of molecules exist in possible alleles that umans are known in humans present peptides to CD8 T cells present peptide to CD4 T cells greater diversity in HLA I than HLA II  MHC : inherited Class II MHC diversity Class I MHC each a chain of HLA DP, DQ, and DR each a chain of HLA A, B, and C is encoded by a separate gene (DPA, DQA, is encoded by a separate gene DRA) each b chain of HLA DP, DQ, and DR (A, B, C) is encoded by a separate gene (DPB, DQB, DRB) eles for each MHC gene in a typical individual on chromosome 6 : DPA1 DPB3 DQA1 DQB4 DRA1 DRB1 B2 C1 A3 DPA2 DPB2 DQA2 DQB4 DRA1 DRB3 B1 C3 A3 transcription, transcription, translation translation MHC alleles are codominant: each one is expressed specific allotypes expressed are determined by polymorphisms a person has  HLA haplotypes are very diverse DPA1 DPB3 DQA1 DQB2 DRA1 DRB1 B2 C1 A4 DPA2 DPB2 DQA2 DQB4 DRA1 DRB3 B1 C3 A3 HLA haplotype : the particular combination of HLA alleles found on chromosome 6 in a single human recombination at HLA locus has produced many different haplotypes over time  millions of combinations of HLA class I and II now exist in the human population !  very unlikely 2 people will share the same HLA haplotype MHC genes exhibit codominance, so: min. # HLA isoforms (for T cell presentation) is in homozygote : 3 class I, 3 class II max. # HLA isoforms (for T cell presentation) is in heterozygote : 6 class I, 16 class II  MHC Gene Expression: Homozygotes and Heterozygotes (MHC genes exhibit codominance): HC cluster in homozygote: 1 2 3 1 2 3 DPA1 DPB2 DQA2 DQB2 DRA1 DRB1 B2 C1 A3 DPA1 DPB2 DQA2 DQB2 DRA1 DRB1 B2 C1 A3  3 different class II molecules possible  3 different class I molecules possib HC cluster in heterozygote: 4 possible combinations 4 possible combinations 4 possible combinations of DPA and DPB of DQA and DQB of DRA and DRB 1 2 3 DPA1 DPB3 DQA1 DQB2 DRA1 DRB1 B2 C1 A4 DPA2 DPB2 DQA2 DQB4 DRA2 DRB2 B1 C3 A3 4 5 6  12 different class II molecules possible  6 different class I molecules possib Variation caused by MHC Polymorphisms amino acid differences in MHC occur at sites that contact peptide or TCR  MHC Restriction ach T cell receptor recognizes a unique peptide:MHC combin Peptide Y: Peptide X: GILGFVFTL AFHHVAR from from HIV influenza the specificity of T cells is dictated by the distinct MHC molec a person has and by the peptides that are bound by them  Heterozygote advantage with MHC molecules homozygous at MHC II heterozygous at MHC loci: II loci: dendritic dendritic cell cell bacterium Possible different Possible different peptides presented: peptides presented: ossible unique Possible unique HC II molecules on DCs: MHC II molecules on DCs: ossible unique Possible unique cell clones activated: T cell clones activated: Possible unique pathogen antigens  Possible unique pathogen antigens targeted by immune response: targeted by immune response: MHC heterozygosity delays AIDS progression heterozygous for all HLA loci homozygous for 2 or 3 HLA loci homozygous for 1 HLA locus  Populations Maintain a Diversity of HLA Class I and II Allotypes uencies of HLA alleles in Yucpa population of South Amerindi ersity of HLA allotypes within a population is essential for su ach population will have its own spectrum of HLA allotypes  Transplant Rejection T cells and antibodies can attack non-self organs: T cells that attack self MHC (autologous) are deleted during development, but those that attack NON-self MHC (allogenic) are not deleted ( tolerance) - alloreactive T cells (recognize non-self MHC) : 1-10% of total pool  these will attack a transplanted organ alloreactive antibodies : produced by mother during pregnancy, react to HLA molecules in fetus specific to the father  these can also attack a transplanted organ  Variation caused by MHC Polymorphisms differences in MHC occur in pockets that hold amino acids of peptide - in the peptide, these amino acids are called anchor residues - peptide-binding motif : combination of anchor residues that binds to a particular MHC isoform  different MHC molecules bind distinct peptide binding motifs and therefore hold different peptides