ANTIGEN PROCESSING AND PRESENTATION.pdf

ANTIGEN PROCESSING AND PRESENTATION Dr. Eman Muhammad majeed ANTIGENS RECOGNISION BY T LYMPHOCYTES T lymphocytes recognize peptide antigens that are bound to and displayed by major histocompatibility complex (MHC) molecules of antigen-presenting cells. (i.e. In every individual, different cl...

ANTIGEN PROCESSING AND PRESENTATION Dr. Eman Muhammad majeed ANTIGENS RECOGNISION BY T LYMPHOCYTES T lymphocytes recognize peptide antigens that are bound to and displayed by major histocompatibility complex (MHC) molecules of antigen-presenting cells. (i.e. In every individual, different clones of CD4+ and CD8+ T cells can see peptides only when these peptides are displayed by that individual’s MHC molecules. This property of T cells is called MHC restriction). The cells that capture microbial antigens and display them for recognition by T lymphocytes are called antigen-presenting cells (APCs). Naive T lymphocytes must see the antigens presented by dendritic cells to initiate clonal expansion and differentiation of the T cells into effector and memory cells.  Antigen recognision Major histocompatibility complex (MHC) molecules are expressed on antigen- presenting cells and function to display peptides derived from protein antigens. PROCESSING AND PRESENTATION OF PROTEIN ANTIGENS Extracellular proteins that are internalized by specialized APCs (dendritic cells, macrophages, B cells) are processed in late endosomes and lysosomes and displayed by class II MHC molecules, whereas proteins in the cytosol of any nucleated cell are processed in proteolytic structures called proteasomes and displayed by class I MHC molecules. These two pathways of antigen processing involve different cellular proteins. They are designed to sample all the proteins present in the extracellular and intracellular environments. MHC I Ag presentation pathway MHC II Ag presentation pathway Processing and Presentation of Protein Antigens Processing of Internalized Antigens for Display by Class II MHC Molecules 1. Internalization and digestion of antigens Antigens destined for the class II MHC pathway are usually internalized from the extracellular environment. Dendritic cells and macrophages may ingest extracellular microbes or microbial proteins by several mechanisms, including phagocytosis and receptor-mediated endocytosis. After internalization into APCs, the microbial proteins enter acidic intracellular vesicles, called endosomes or phagosomes, which may fuse with lysosomes. In these vesicles the proteins are broken down by proteolytic enzymes, generating many peptides of varying lengths and sequences. Processing of Internalized Antigens for Display by Class II MHC Molecules (cont.) 2. Binding of peptides to MHC molecules. Peptides bind to newly synthesized MHC molecules in specialized vesicles. 3. Transport of peptide-MHC complexes to the cell surface. Peptide loading stabilizes class II MHC molecules, which are exported to the cell surface. Endocytic pathway Endocytic pathway Processing of Cytosolic Antigens for Display by Class I MHC Molecules 1. Proteolysis of cytosolic proteins. The peptides that bind to class I MHC molecules are derived from cytosolic proteins following digestion by the proteasome pathway. Antigenic proteins may be produced in the cytoplasm from viruses that are living inside infected cells, from some phagocytosed microbes that may leak from or be transported out of phagosomes into the cytosol, and from mutated or altered host genes that encode cytosolic or nuclear proteins, as in tumors. Processing of Cytosolic Antigens for Display by Class I MHC Molecules(cont.) 2. Binding of peptides to class I MHC molecules. In order to form peptide-MHC complexes, the peptides must be transported into the endoplasmic reticulum. 3. Transport of peptide-MHC complexes to the cell surface. If a class I molecule finds a peptide with the right fit, the complex is stabilized, and transported to the cell surface. Cytosolic Pathway Cytosolic Pathway In summury The role of MHC molecules in antigen display ensures that T cells only recognize cell-associated protein antigens and that the correct type of T cell (helper or cytotoxic) responds to the type of microbe the T cell is best able to combat. Microbes activate APCs to express membrane proteins (costimulators) and to secrete cytokines that provide signals that function in concert with antigens to stimulate specific T cells. The requirement for these second signals ensures that T cells respond to microbial antigens and not to harmless, non microbial substances. B lymphocytes recognize proteins as well as non protein antigens, even in their native conformations. Follicular dendritic cells display antigens to germinal center B cells and select high-affinity B cells during humoral immune responses. Induction of immune responses In fact, the immune system has to react in different ways even to the same microbe at different stages of its life. The first mechanism Involve the defense against a microbe that has entered the circulation and is free in the blood, This mechanism depends on antibodies that bind the microbe, prevent it from infecting host cells, and help to eliminate it. The production of potent antibodies requires the activation of CD4+ helper T cells. The other mechanism When the Ag (the microbe) infect the host cells. It is safe from antibodies, which cannot enter the cells. As a result, activation of CD8+ cytotoxic T lymphocytes (CTLs) may be necessary to kill the infected cells and eliminate the reservoir of infection. Cross-Presentation of Internalized Antigens to CD8+ T Cells some viruses may infect only particular cell types and not dendritic cells, and these infected cells may not travel to lymph nodes or produce all the signals needed to initiate T cell activation. How, then, are naive CD8+ T lymphocytes in lymph nodes able to respond to the intracellular antigens of infected cells? Similarly, tumors arise from many different types of cells, so how can diverse tumor antigens be presented to naive CD8+ T cells in lymph nodes by dendritic cells? What is cross presentation? A subset of classical dendritic cells has the ability to ingest infected host cells, dead tumor cells, microbes, and microbial and tumor antigens and transport the ingested antigens into the cytosol, where they are processed by the proteasome. The antigenic peptides that are generated then enter the ER and bind to class I molecules, which display the antigens for recognition by CD8+ T lymphocytes. This process is called cross-presentation (or cross-priming), to indicate that one type of cell, dendritic cells, can present the antigens of other infected or dying cells or cell fragments and prime (or activate) naive CD8+ T lymphocytes specific for these antigens. Once the CD8+ T cells have differentiated into CTLs, they kill infected host cells or tumor cells without the need for dendritic cells or signals other than recognition of antigen. Cross presentation of Ag by dendritic cells