4-Antigen Processing and Presentation_SAH.pdf

Antigen Processing and Presentation Click to edit Master subtitle style IMMC  Objectives ▪ Compare the structure and expression of MHC class I and II (proteins). ▪ Describe the role MHC in regulating the immune response. ▪ D...

Antigen Processing and Presentation Click to edit Master subtitle style IMMC  Objectives ▪ Compare the structure and expression of MHC class I and II (proteins). ▪ Describe the role MHC in regulating the immune response. ▪ Discuss the source and types of antigen processed by class I and II molecules. ▪ List professional antigen presenting cells. ▪ Discuss the role of the T helper cell in both cell- mediated and humoral immunity.  Introduction ▪ Antigen Recognition by T and B cells: ▪ B cells recognize free antigens using antibodies. ▪ T cells recognize antigens as peptides presented on cell surfaces by MHC molecules. ▪ Major Histocompatibility Complex (MHC): ▪ Encoded by the MHC locus genes. ▪ Acts as a cell-surface vessel to present antigen fragments. ▪ Essential for T-cell engagement via their receptors. ▪ MHC Importance and Discovery: ▪ Named for its role in tissue transplant acceptance or rejection. ▪ 1980 Nobel Prize awarded for discoveries on MHC's role in organ transplants and immune responses.  Introduction ▪ Classes of MHC Molecules: ▪ Class I and II: ▪ MHC class I in human is known as HLA class I and MHC class II is known as HLA class II. ▪ Similar shapes, present antigens to T cells but differ in roles and structure. ▪ MHC Structure, Function, and Expression: ▪ Discussion of MHC class I and II structures, genetic organization, and inheritance. ▪ Regulation of MHC gene expression and its role in immunity. ▪ Antigen Processing and Presentation: ▪ Pathways of antigen degradation, association with MHC molecules. ▪ Presentation of these complexes on cell surfaces for T-cell recognition. ▪ Includes unique pathways like cross-presentation and handling of nonpeptide antigens.  Antigens Capturing and Processing ▪ Cells encounter the antigens upon crossing the physical barriers and then capture the antigens to engulf the antigens leading to its appearance in either in the cytosol or in a vesicle. ▪ Once a pathogen is inside a cell it needs to be degraded into protein peptides in a sequence event and associate with an MHC molecule.  Antigens Presentation ▪ Once an antigen is degraded it needs to be transported to the surface of the cell and displayed within a cleft of an MHC molecule in order to be recognized by TCR on the T lymphocyte. T Cell APC  Antigens Presentation ▪ Once an antigen is degraded it needs to be transported to the surface of the cell and displayed within a cleft of an MHC molecule to be recognized by TCR on the T lymphocyte. ▪ List of Antigen Presenting Cells ▪ Macrophages Antigen Presenting Cells ▪ Dendritic Cells ▪ B cells  What is Major Histocompatibility Complex (MHC)? ▪ MHC is a set of cell surface molecules encoded by a large genetic complex with multiple loci. ▪ The MHC loci encode 2 major classes of membrane-bound glycoprotiens: ▪ 1. MHC class I ▪ 2. MHC class II ▪ MHC function: ▪ The major function of MHC is to bind to “processed antigen peptides” displayed on the cell surface to be recognized by specific T lymphocytes to initiate an immune response.  MHC Class I & II ▪ MHC Class I Molecules: ▪ Found on all nucleated cells. ▪ Present peptides derived from endogenous proteins. ▪ Interact with CD8+ T cells. ▪ MHC Class II Molecules: ▪ Expressed mainly on professional APCs (dendritic cells, macrophages, B cells). ▪ Present peptides derived from exogenous proteins. ▪ Interact with CD4+ T cells.  Structure of MHC Class I & II ▪ MHC class I: Consist of 4 domains ▪ (1, 2, 3 and β2-microglobuline) ▪ Is expressed on all cell types ▪ except unnucleated cells (Red Blood Cells) MHC Class I MHC Class II ▪ And is recognized by CD8+ cytotoxic T cells. ▪ MHC class II: Consist of 4 domains ▪ (1, 2, β1and β2) ▪ Is only expressed on antigen presenting cells ▪ (Dendritic cells, Macrophages, B lymphocytes) ▪ And is recognized by CD4+ helper T cells (Th).  Human Leukocyte Antigen (HLA) ▪ The Major Histocompatibility Complex in human is known as the human leukocyte antigen (HLA). MHC class I in human is known as HLA class I and MHC class II is known as HLA class II. ▪ HLA class I and class II are polygenic (several loci encoding products with essentially the same function) ▪ HLA class I: HLA-A, HLA-B and HLA-C ▪ HLA class II: HLA-DR, HLA-DP and HLA-DQ ▪ HLA class I and class II are polymorphic (variability of alleles in the species) ▪ There are > 2000 HLA-A alleles , > 3000 HLA-B alleles and > 2000 HLA-C alleles. For example HLA-A2, HLA-A26 and HLA-B50  Types of Presented Antigens ▪ Endogenous antigens are degraded into peptides within the cytosol by proteasomes and assembled with MHC class I. ▪ For example: viruses and tumours. ▪ Exogenous antigens are internalized and degraded within endocytic compartments and subsequently assembled with MHC class II. ▪ For example: bacteria  Endogenous antigens: Processing and Presentation ▪ Process by which cells present internal, cellular proteins to T cells. ▪ Protein Degradation: ▪ Cytosolic proteins tagged for degradation by ubiquitin. ▪ Proteasome (immunoproteasome in immune cells) cleaves proteins into peptide fragments. ▪ Peptide Transport: ▪ Peptides transported from cytosol to Endoplasmic reticulum (ER) by transporters associated with antigen processing (TAP) molecules. ▪ TAP preference for peptides 8-10 amino acids in length. ▪ Then they get loaded into MHC class I and transported to the surface of the cell. Kuby Immunology (8th ed)  Endogenous antigens: Processing and Presentation ▪ MHC Class I Loading: ▪ In the ER, peptide fragments bind to newly synthesized MHC Class I molecules. ▪ The peptide-MHC Class I complex is stabilized by the addition of β2- microglobulin. ▪ Transport and Expression on Cell Surface: ▪ Complexes are transported to the Golgi apparatus, then to the cell surface. ▪ Presented antigens are now available for recognition by CD8+ T cells.  Exogenous Antigens: Processing and Presentation ▪ Process by which cells present external, non-cellular proteins to T cells. ▪ Antigen Uptake: ▪ Antigens are internalized through phagocytosis or endocytosis. ▪ Encapsulated in vesicles that fuse with lysosomes. ▪ Antigen Processing: ▪ In lysosomes, antigens are degraded into peptide fragments. ▪ Acidic environment and lysosomal enzymes facilitate the breakdown.  Exogenous Antigens: Processing and Presentation MHC Class II Loading: MHC Class II molecules synthesized in ER with an invariant chain that blocks the peptide- binding groove. In endosomes, invariant chain is cleaved, leaving Class II-associated invariant chain peptide (CLIP) in the groove. Peptide-MHC Class II Complex Formation: CLIP is removed and peptides bind to the MHC Class II molecules. The stable peptide-MHC Class II complexes are transported to the cell surface.  Exogenous Antigens: Processing and Presentation Endosome containing degraded Peptides binds to protein (i.e., MHC class II. MHC peptides) fuses with class II + peptide are endosome displayed on the cell containing MHC surface class II  MHC Restriction ▪ Phenomenon where T cells recognize antigenic peptides only when presented in conjunction with MHC molecules. ▪ T Cell Recognition: ▪ T cell receptors (TCRs) are designed to recognize a complex of peptide and MHC molecule, not peptide alone. ▪ Specificity towards MHC-peptide complexes ensures that T cells can effectively monitor cellular processes. ▪ Role in Immune Response: ▪ Ensures that T cells only respond to peptides displayed on self-MHC molecules, crucial for distinguishing self from non-self. ▪ Central to the immune system's ability to target infected or dysfunctional cells without harming normal body cells.  Clinical Relevance ▪ Transplantation Compatibility: ▪ MHC molecules are major determinants in organ and tissue transplant compatibility. ▪ Mismatches in MHC can lead to transplant rejection. ▪ Autoimmune Diseases: ▪ Certain MHC genotypes are associated with higher risks for autoimmune diseases like Type 1 diabetes and rheumatoid arthritis. ▪ Infectious Diseases: ▪ MHC diversity influences susceptibility to infections and the outcome of diseases like HIV and malaria. ▪ Cancer Immunotherapy: ▪ Understanding MHC involvement in presenting tumor antigens can enhance the effectiveness of cancer vaccines and adoptive T cell therapies. ▪ Personalized Medicine: ▪ MHC profiling can guide personalized medicine approaches, tailoring treatments based on individual MHC makeup to enhance efficacy and reduce adverse effects. 19 Thank you 20