How does our body defend itself? Lecture 18-2 Essentials of Immunology CHAPTER 22 in BROCK BIOLOGY OF MICROORGANISMS School of Life Science and Biotechnology, http://micro.sjtu.edu.cn
18.5 Presentation of Antigens to T Cells 抗原向 T 细胞的呈递 T cells interact specifically with antigen through the cell-surface (T-cell receptor). T-cell receptors (TCRs) interact with antigens held in place on antigen-presenting cells ( 抗原提呈细胞 ) through major histocompatibility complex ( 主要组织相容性复合体, MHC) proteins.
Molecular basis of specific immunity T cell receptors The T-cell receptor is a membrane-spanning protein that extends from the T cell surface into the extracellular environment. A functional TCR consists of two proteins, an α chain and a β chain. Each of thesis chains has a variable (V) domain and a constant (C) domain. The Vα and Vβ domains cooperate to form a complete antigen-binding site.
Structure of the T-cell receptor (TCR). The V domains of the α chain and β chain combine to form the peptide antigen-binding site
Major Histocompatibility proteins Major histocompatibility complex (MHC): a genetic region encoded MHC proteins in all vertebrates. 主要组织相容性复合物 MHC proteins function as antigen-presenting molecules and interact with both the antigen and the TCR. MHC proteins are not structurally identical within a given species. Different individuals often show subtle differences in the amino acid sequence of their MHC molecules.
Structures of the two types of MHC proteins. (a) Class I MHC protein. The α 1 and α 2 domains interact to form the peptide antigen-binding site. Found on the surfaces of all necleated cells. (b) Class II MHC protein. The α 1 and β 1 domains combine to form the peptide antigen-binding site. Found only on the surface of B cell, macrophages, and other antigen-presenting cells (APCs).
Class I antigen presenting pathway the class I proteins are made and assembled in the endoplasmic reticulum. 1) Protein antigens manufactured within the cell, for 2.) The peptides then bind to instance from viruses or tumors, class I, are transported to the are 4.) The degraded CD8 coreceptor in the cytoplasm on the cell surface, and and T C cell transported also engages across the the class I endoplasmic 3.) MHC, interact resulting with reticulum in T-cell a stronger membrane. receptors complex. The (TCRs) T C cells on then surface release of cytokines T c cells. and cytotoxins, proteins that kill the target cell. FLASH
Class II antigen presenting pathway 1.) class II proteins are produced in the endoplasmic reticulum 2.) Class II then goes to the and are assembled with a phagolysosome blocking 3.) The class protein, II protein where Ii (invariant then Ii and foreign proteins, 4.) chain), binds which prevents class II imported The to complex the digested from outside interacts foreign the cell with from peptides, complexing with other peptides (by endocytosis), TCRs and and the complex is transported found in the the are cell endoplasmic digested. surface reticulum. 5.) the CD4 coreceptor ont H cells. The T H cells then release cytokines that act on other cells to activate an immune response. FLASH
18.6 T-cytotoxic cells and Natural killer cells 细胞毒 T 细胞与自然杀伤细胞 Tc cells are involved in the destruction of cells that display foreign antigens on their surface.
T c cells, are activated by antigens presented on any cell in the context of MHC I protein. The T c cells release granules that contain perforin 穿孔素 and granzymes 颗粒酶, cytotoxins 细胞毒素 which perforate the target cell and cause apoptosis, respectively
Natural killer cells NK cells are neither T cells nor B cells. NK cells resemble Tc cells in their ability to kill foreign cells. (e.g. use perforin and granzymes to kill targets) NK cells differ from Tc cells in that they kill targets in the absence of recognition of a specific antigen. The molecular target for Nk cells seems to be the lack of appropriate MHC class I proteins.
18.7 T-helper cells: activating the immune response Macrophage Activation Macrophages bind, process, and present antigen to T H 1 cells. T H 1 cells in turn can use cytokines such as interferon gamma to activate macrophages to kill intracellular bacteria Moderate dose of M. Tuberculosis to induce T cell mediated immunity to bacterial pathogens
T-inflammatory cells, or T H 1cells, are activated by antigens presented on macrophages in the context of MHC II protein. The T H 1 cells respond by producing cytokines that stimulate the macrophages to increase phagocyte activity and promote inflammation
The role of T cells in specific immunity
III. Humoral immunity 体液免疫 Process: Antigen-antibody recognition Antibody production by B cells stimulated by T H 2 cells
18.8 Antibodies (Immunoglobulins) Protein molecules that are able to combine with antigenic derminants. Five major classes: IgG IgA IgM IgD IgE
Immunoglobulin G IgG consists of two heavy chains (50,000 molecular weight) and two light chains (25,000 molecular weight), with a total molecular weight of 150,000. One heavy and one light chain interact to form an antigenbinding unit
Immunoglobulin G (IgG) The most abundant immunoglobulin, 80% Two antigen binding domains, bivalent Light chain-one variable domain, one constant domain Heavy chain-one variable domain, three contant domains
Immunoglobulin G (IgG)
(a)igg, IgA, and IgD have three constant domains (blue). (b) IgM and IgE each have a fourth constant domain Immunoglobulin classes. All classes of immunoglobulins have VH and VL domains (red) that bind antigen (brown).
Immunoglobulin M (IgM) is found in serum as a pentameric protein consisting of five IgM proteins covalently linked to one another via disulfide bonds and a J chain protein
Immunoglobulin A Structure Secretory immunoglobulin A (siga) is often found in body secretions as a dimer consisting of two IgA proteins covalently linked to one another via a J chain protein.
18.9 Antibody production T cell-b cell interaction: The production of immunoglobulins in response to antigen involves interactions between T cells and B cells through their respective antigen-specific cell surface molecules.
B cell functions as an antigen-presenting cell (APC) and concentrates antigen using anigen-specific immunoglobulin receptors. After processing, antigen is presented to the T H 2 cell by a class II MHC molecule. The T H 2 cell then signals the same B cell to proliferate and form plasma cells or memory cells. After subsequent antigen exposure, memory cells quickly convert to plasma cells T cell B cell interaction and antibody production
The secondary response, also called a booster response, may be more than tenfold greater than the primary response. Note the class switch from IgM production in the primary response to IgG production in the secondary response
18.10 Complement Functions 补体功能 Complement is a series of proteins that are activated by interactions with antigen-antibody complexes. Complement catalyzes the bactericidal and lytic actions of antibodies against many gramnegative bacteria. Activation of complement occurs only with antibodies of the IgG and IgM classes.
Complement activation 补体活化 The sequence, orientation, and activity of the various components as they interact to lyse a cell. Panel 1: Binding of the antibody recognition unit C1q and other C1 proteins; panel 2: the C4-C2 complex; panel 3: the C4-C2-C3- C5 complex after activation, the C5 unit travels to an adjacent membrane site; panel 4, binding of C6, C7, C8, and C9, resulting in membrane damage
Lysis by complement Three-dimensional view of the hole formed by complement components C5 through C9.
Important questions on the immune response 1. How can a T cell tell self from nonself antigens? 2. How can the B cells produce so many different kinds of antibodies? 3. What can we do with our understanding on the molecular and cellular mechanisms of immune reactions in our body?
Question1: How can T cells tell self from non-self?
How can the T cells tell self from nonself antigens? (Immune Tolerance) MHC Proteins serve as molecular reference points that permit T cells to identify foreign antigens MHC molecules act as a platform on which the foreign antigen is bound TCRs can bind MHC and recognize foreign antigens embedded in the MHC structure
T-cell Selection and Tolerance T cells undergo selection for antigen-reactive T cells and selection against clones that react with self antigens.
T-cell selection and clonal deletion. T cells undergo a stepwise selection process in the thymus
Question2: How can the B cells produce so many different kinds of antibodies?
Clonal selection 克隆选择学说 Clonal selection is a hypothesis stating that each antigen-reactive B cell or T cell has a cell-surface receptor for a single antigen.
Individual B cells, specific for a single antigen, proliferate and expand to form a clone after interaction with the specific antigen. The specific antigen acts as the selection agent, driving selection and then proliferation of the individual antigen-specific B cell.
Clonal copies of the antigen-reactive cell all have the same antigen-specific surface receptor. Continued exposure to antigen results in continued expansion of the clone
Detailed structure of IgG
Gene rearrangement: genes in pieces hypothesis 基因重排 A single light or heavy chain is actually encoded by several genes. Genes for V, D, J, and C regions were separated from aone another in the genome. 150 V genes, 5 J genes, 5 C genes for light chain 200 V genes, 50 D genes, 4 J genes, 2 C gene for heavy chain
Formation of active gene for heavy chain via somatic recombination
Formation of active gene for light chain via somatic recombination
Somatic Diversity Possible antibody genes Light chain-750 kinds; Heavy chain-4000 kinds the combination-3,000,000 kinds Imprecision in the joining at VDJ fusion D region in heavy chain can be read in three reading frames Hypermutation: the mutation of Ig genes is at higher rates than the mutation rates observed in other genes. The number of possible antibody-infinite
Learning to be more precise
Question3: What can we do with our understanding on the molecular and cellular mechanisms of immune reactions in our body?
Monoclonal antibody 单克隆抗体 Antibody preparation which can only react with one determinant Producing one kind of antibody using an impure antigen High specificity and reproducibility in reaction
Monoclonal antibody 单克隆抗体 Each antigen-activated B cell is genetically programmed to become a clone that produces a monoclonal antibody, but many B cells mix together normally to produce polyclonal antibodies Monoclonal antibody can only be produced with laboratory technology-hybridoma technique 杂种瘤技术
Hybridoma technique 杂交瘤技术 B cell can produce antibody but can not grow indefinitely in culture Myeloma (tumor) cell 骨髓瘤细胞 can grow indefinitely in culture but does not produce antibody Cell fusion between B cell and Myeloma cell to form hybrid cell line which can grow indefinitely in culture and produce one kind of antibody FLASH
Hybridoma technique for monoclonal antibody production
Monoclonal antibody and cancer therapy Tumor cells express unique antigens such as those expressed in fetal development Monoclonal antibodies can be prepared against these tumor specific antigens Detection of cancer cells with monoclonal antibody Treatment of cancer cells with monoclonal antibody covalently conjugated with cell toxins