Lecture 32 Adaptive Immunity 2024 PDF

7. Complement Complement system – 30 proteins produced by the liver, circulate in serum recognize pathogens to trigger activation Once activated, other components… – Induce inflammation – Signal to attract immune cells – Bind the pathogen to enhance destruction...

7. Complement Complement system – 30 proteins produced by the liver, circulate in serum recognize pathogens to trigger activation Once activated, other components… – Induce inflammation – Signal to attract immune cells – Bind the pathogen to enhance destruction by phagocytic cells via opsonization – Lyse the pathogen Nature Immunology 11, 785–797 (2010)  Opsonization Complement protein C3b or antibodies bound to the surface of an invading bacterium act as opsons Promote adherence and ultimately phagocytosis  Complement activation: “Alternative pathway” shown here C3 b a b MORE PHAGOCYTES! MORE PHAGOCYTES! 5b b Bacterium C5 Membrane attack complex Complement activation requires several accessory factors that are not shown here!  Innate immunity – Summary I AMPs/lysozyme/lipases EAT! TLR4 cytokines e.g. LPS Bacterium MAMPs phagocytic cell (or flagellin, HELP LTA, CpG…) KILL! Complement proteins Transmigrate, ATTACK!!! MAMPs = microbe-associated molecular patterns All clear?  Innate immune components summary II Barriers Cellular components Thick epithelium Phagocytic cells Tight junctions (neutrophils, macrophages, Chemical attack dendritic cells) Lysozyme AMPs Complement proteins C3, C5 and helpers  Summary III The innate immune system is the unsung hero of our defenses against potential pathogens Mechanical, chemical and microbiota barriers are the first line of defense against microbial invasion Acellular responses include the production of antimicrobial peptides by certain cell types, also complement in the serum that can help identify and neutralize invaders Cellular responses include recognition of microbial molecular signals (PAMPs or MAMPs) by receptor proteins on immune cells. Recognition then activates and mobilizes appropriate responses. One response to invaders includes the release of cytokines and chemokines to initiate the inflammatory response.  Adaptive Immunity 1. Adaptive immune response introduction: B-cells, T-cells and antibodies 2. B cells and memory 3. T cells 4. Cell mediated immunity  Innate immunity Adaptive immunity 500 1st exposure 2nd exposure 1st 1st exposure 2nd exposure immune cells/functions 500 400 immune cells/functions 400 300 300 200 200 100 100 0 0 0 5 10 15 20 00 10 10 20 30 time time Done! You know this stuff inside and out  1. Adaptive Immune Response – the main players Lymphocytes: T lymphocytes (T cells), cell-mediated response B lymphocytes (B cells), humoral responses (antibody) Antibodies are made by B-cells Old friends: Cytokines (as signals)  Antibody architecture - Antibodies recognize diverse non-host structures. - They contain variable regions that can bind a variety of antigens - Each antibody recognizes a unique epitope Antibodies recognize foreign particles Antigen – a compound (e.g. protein) recognized as foreign, this recognition activates a lymphocyte and leads to an adaptive immune response Epitope – tiny portion of an antigen that interacts with and is recognized by antibodies  The humoral response neutralizes threats through antibody binding Three major ways antibodies (immunoglobulins) clear an infective agent: Opsonization Neutralization Complement activation = ONC Antibodies are broadly used to neutralize toxins, for example in snake antivenom!  2. B-cells and the humoral immune response B-cells are produced in the bone marrow and carry antibodies (“B-cell receptors”) on their surface. Once its BCR binds a specific antigen, B cells can differentiate into Plasma cells (and memory cells!) Plasma cells produce antibodies But how does an antibody know its antigen? B-cells with almost infinite antibody diversity are produced in the bone marrow In the bone marrow, self-reactive B-cells are weeded out through clonal deletion new antigen Antigen binding (+ helper cell!) activates B-cells Clonal propagation + Refinement (”somatic hypermutation”) new antigen differentiation Memory B-cell  Memory B-cells rapidly react after second exposure to same antigen Memory B-cell  3. T-cells and the cell-mediated immune response T-cells are produced in the bone T-cells bind to special receptors marrow and carry T-cell (MHCI and II) on Antigen receptors on their surface. presenting cells (APCs) T-helper Cytotoxic T-cell Once its TCR binds a specific antigen on another cell, different T-cell types either signal (cytokines) or kill an infected cell How does the T-cell meet its antigens? – by talking to antigen presenting cells! (APCs, e.g. phagocytes) dendritic cell MHC II Major Histocompatibility Complex APCs present antigens to T cells via Major Histocompatibility complexes (MHCs) CD4 co-receptor CD8 co-receptor - MHC II on antigen- on T cell on T cell presenting cells interacts with and activates T-helper cells (co-receptor on T-cell: CD4) - MHC I on infected cells interacts with and activates Cytotoxic T- cells (co-receptor on T- cell: CD8) APC or B cell APC or Infected cell APC, Antigen Presenting Cell  T cell activation An APC displays an antigen on the MHCII receptor protein on the cell surface. It also produces signals to CD4 CD8 attract naïve T cells. A helper T cell with a receptor that recognizes the antigen is activated. This effector T cell divides (some become memory T cells).  Why do we need T-helper cells? To activate B-cells, for example! In order to differentiate into Plasma and Memory cells, B- cells need to be activated by T- helper cells!  Why so complicated? Why do you need two events (recognition by B-cell and T-helper) to elicit an immune response?  Cell Mediated Immunity In cell-mediated immunity, activated effector T Cells release cytokines to activate Cytotoxic T Cells Any cell can display an antigen on the MHCI receptor protein on the cell surface. A cytotoxic T cell with a TCR CD8 receptor that recognizes the antigen (stabilized by CD8) is activated. (some become memory T cells). The cytotoxic T cell kills the infected cell. But how does a T-cell receptor know its antigen? Self-reactive T cells are removed in the Thymus. Naïve T-cell Figure 27.2 Where do T-cells and APCs meet? Lymphoid Tissues and Lymphatic Circulation Lymphoid precursor cells differentiate into B or T cells in the Bone marrow or Thymus. These immature (naïve) lymphocytes are carried to peripheral lymphoid organs (in blue) These are locations where they can interact with specific antigens => maturation. Cytotoxic T cell – searching for target, then delivering perforin and granzymes to target cell Immunity (2015) Putting it all together… humoral response Pathogen (virus/bacterium) B- cells Phago -cytes MHCII Th cell memory (CD4+) B-cell ONC: Opsonize Neutralize Complement  Putting it all together… cell-mediated response Pathogen (virus/bacterium) Any cell MHCI cT-cells (CD8+) (left out for dramatic purposes: cytotoxic T-cell activation also requires a T-helper cell!)  Summary The humoral response is mediated by B-cells and antibodies (antibodies neutralize toxins and pathogens) The cell-mediated response relies on T-cells. T-cells come in two varieties: Cytotoxic T-cells that kill infected cells, and helper T-cells that activate B-cells (among other things) The immune system generates pathogen-reactive B- and T-cells through a random change process The immune system exhibits memory function, but differentiating some B and T-cells into long-lived memory cells that can reactivate once they encounter the same pathogen again