Immunology Lecture 7 Antigen PDF

Lesson 7 Learning Objectives: 7a.Recognize KEY NON-MICROBIAL antigens 7b: Recognize/differentiate the two pathways of antigen processing and presentation (exogenous and endogenous pathways) and their importance 7c: Recognize and differentiate the characteristics/function of the three professiona...

Lesson 7 Learning Objectives: 7a.Recognize KEY NON-MICROBIAL antigens 7b: Recognize/differentiate the two pathways of antigen processing and presentation (exogenous and endogenous pathways) and their importance 7c: Recognize and differentiate the characteristics/function of the three professional/semi-professional Antigen Presenting Cells (APCs) Professional Antigen Presenting Cells Nonmicrobial antigens: Molecules expressed on the surface of normal cells that in another animal could stimulate an immune, are also referred to as antigens… cell surface antigens. Examples: o Blood group antigens. Glycoproteins of glycolipids on the surface of red blood cells (RBCs)… Already covered. o Major Histocompatibility Complex molecules (MHC). ▪ Protein molecules expressed on the surface of all nucleated cells…NOTE: MHC-I molecules can be induced to be expressed on all nucleated cells. MHC-II molecules are only expressed on Antigen-Presenting Cells (Professional APCs = Dendritic Cells, Macrophages… and B-lymphocytes)… to be discussed later. ▪ The MHC molecules are very important in recognition and signaling events for generating an adaptive immune response. Will discuss in detail later. ▪ Are also important for tissue recognition, transplantation medicine o Cluster of Differentiation (CD) molecules ▪ Surface molecules (antigens) on immune cells. Expression of these molecules on lymphocytes is used to define subsets of lymphocytes. 1 ▪ The CD molecules can be identified by using monoclonal antibodies (MoAb) made against these CD antigens. For example, we can make a MoAb in a pig that recognizes the CD4 molecule express on horse lymphocytes. ▪ Each CD molecule denotes a protein with a specific function: CD4 is expressed by a subset of T-lymphocytes that have “helper” function CD8 is expressed on a subset of T-lymphocytes that “kill” abnormal cells. CD25 is a molecule expressed on a number of different types of cells and its function is to bind IL-2. (CD25 is also called the IL- 2R). Thus, any cell expressing CD25 can respond to IL-2. 2  ESSENTIALS OF THE ADAPTIVE IMMUNE RESPONSE A good video to watch as an overview of the adaptive immune response:… will not cover suppressor T-cells part discussed at the end of this video. https://www.youtube.com/watch?v=nqRn5fN22t4 Recommend watching at the beginning of this section on adaptive immunity… AND at the end…. And again as a review after covering all aspects of Adaptive Immunity. Will not cover the suppressor T-cells. THE BIG PICTURE … ANTIGEN-PROCESSING (Of PROTEINS) AND PRESENTATION (of PEPTIDES) O ANTIGEN-SENSITIVE CELLS. Professional Host APCs…. Where microbe replicates Non-professional and makes microbial (Dendritic cells, Host infected macrophages, antigens cells/tumor cells: B-cells)… MHC-II molecules MHC-I molecules Important in Important in antigen presentation antigen presentation T-helper CTLs (cytotoxic Cells. Cytokines T-cells) help both B-cells Cells and CTLs End result is End result is activated CTLs mainly and Cell-mediated Immunity Antibody Ability to kills infected cells production… and Tumor cells. Humoral Immunity 3  Consider: What is the significance of having these two pathways of antigen processing/presentation??? Antigen: Already covered Antigen Processing/Presenting Cells Professional … and semi-pro APCs (Antigen Processing/Presenting Cells)… : Process and present Exogenous antigen. Exogenous antigen needs to be acquired and presented to T-lymphocytes (a specific subset of T- lymphocytes called CD4+ T-helper cells) by Professional and semi-pro APCs. o Dendritic cells (PRO APCs) o Macrophages (semi-pro) o B-lymphocytes (semi-pro) Non-professional antigen presenting/processing cells: Host infected cells and host tumor cells… can process and present endogenous antigen to CTLs (All mature CTLs express CD8 on their surface… o Any host cell with a nucleus can process and present endogenous antigens (made inside that cell due to the cell being infected or because the cell is a tumor cell) to a CTL with aTCR that recognizes that antigen. MHC molecules: o Pro and semi-pro APCs present EXOGENOUS antigen to T-helper lymphocytes by first processing the microbial antigen, loading the antigen into an MHC-II molecule, then shuttling the MHC-II-Ag complex to its surface for presentation. T-helper lymphocytes can only “see” antigen if being presented on the surface of an APC within the context of self-MHC-II molecules. o Any nucleated host cell that is infected by intracellular pathogens (or a tumor cell that is making tumor antigens that are ‘foreign’ to the host) can process and present ENDOGENOUS microbial/tumor antigens to cytotoxic T-lymphocytes (CTLs) via MHC-I molecules. However, only APCs can take up, process and present EXOGENOUS antigen via MHC-II molecules. B- and T-lymphocytes B-cells have a B-Cell Receptor (BCR) on the surface that can recognize (interact with) soluble, free in solution antigen. T-cells have a T-Cell Receptor (TCR) on the surface that can recognize antigen ONLY when presented by an APC or an infected, nucleated cell within the context of self-MHC molecules. Usually, B-lymphocytes need help (cell-to-cell interactions and cytokines) from helper T-lymphocytes to make antibody. They make antibody that is specific for the antigen that the B-cell recognized initially. 4  T o roups of ost Cells t at present anti en to T l mp oc tes. T e Pro and semi pro APCs present e tracellular anti ens forei n proteins t at t e en ulf from t e e tracellular E tracellula en ironment) and present peptide r icro es or micro ial fra ments to T elper cells onl fra ments endritic Cells acrop a es and B l mp oc tes.. Host infected cells and Host tumor cells T ese cells contain forei n proteins t at orei n proteins are made inside t e ost cell from made inside t e ost cell intracellular replicatin micro es or made tumor cell). T ese cells present peptide fra ments enerated inside of t em) to C toto ic T cells CT s). an Host infected or Host tumor cell it a nucleus Note the MHC molecule on the cell presenting peptides to the T-lymphocyte. If the cells is a pro/semi-pro APC, then the MHC molecule will be an MHC-II molecules and the presentation will be to a T-helper cell If the cell is a host infected or tumor cell, then the MHC molecule will be an MHC-I molecule and the presentation will be to a CTL 5  Exogenous antigen Host infected Host APCs…. cells/tumor cells: (Dendritic cells, macrophages, APCs (antigen MHC-I molecules B-cells)… Important in presenting cells) antigen presentation T-helper CTLs (cytotoxic Cells T-cells) Cells End result is Antibody production by B- End result is activated CTLs cells… Antibody is the Acquired Humoral and Cell-mediated Immunity Immune product Ability to kills infected cells and Tumor cells. Professional (and semi-pro) Antigen Presenting Cells: The subset of Antigen Processing Cells that can process exogenous antigen and present antigen via MHC-II molecules to Th-cells. Full-time professional APC: Dendritic cells onlyjob Semi-pro APCs: Macrophages APCandphagocytic B-lymphocytes NOTE that these cells can do other things as well. 6  EXAMPLE using a macrophage as an APC: Presentation of exogenous antigen to a T-helper cell I Ag presentation to helper T-lymphocytes Antigen Antigen presenting cell MHC-II molecules Lymphocyte with receptor (TCR) Professional (and semi-Pro) Antigen Presenting Cells: The subset of Antigen Processing Cells that can process exogenous antigen and present antigen via MHC-II molecules to Th-cells. Dendritic cells Macrophages B-lymphocytes NOTE that these cells can do other things as well. Dendritic cells (DCs): The KEY APC. The Star Professional APC. o Full time professional antigen processing cells. o Much more effective (>100X) as an APC than macrophages and B cells. Mature DCs are best for processing and presenting antigen. Immature DCs are good at antigen capture. o Can take up many kind of antigens (dead microbes, soluble antigens, antigens released by dying cells) o Found in all organs except the brain, parts of the eye and testes. Prominent in lymph nodes, skin, and all mucosal surfaces where invading microbes are likely to be encountered. o After antigen capture, immature DCs migrate to lymph nodes where they mature and process Ag to present to lymphocytes. 7 o The only APC that can present and activate T cells that have never encountered antigen before (naïve T-cells). Thus, they are essential for initiating the primary immune response. o Produced from bone marrow stem cells. o Long, thin cytoplasmic processes called dendrites o FYI: Some types of DCs ▪ Langerhans cells – immature DC that reside in the skin (origin of histiocytoma in dogs) ▪ Interdigitating dendritic cells – mature DC that interact with T cells in the lymph node ▪ Thymic dendritic cells – reside in thymus. Important for negative selection of T cells that recognize self antigens. (recognize and kill self-reacting T-cells in Thymus) 8  Other APCs (often referred to as Semi-Professional APCs) (Naïve T cells first respond to dendritic cells. Once activated, they become responsive to macrophages and B cells.) o Macrophages ▪ Remember that macrophages have several functions in addition to being semi-professional APCs… for example, they are phagocytic cells. ▪ Can only present antigen to previously sensitized T-helper cells. o B-cells ▪ Their main function is to make antibody. ▪ Have receptors on their surface that can bind antigen. This is the B-Cell Receptor (BCR). The BCR is membrane-bound antibody: The BCR can bind soluble antigen molecules (proteins mainly but also polysaccharides and lipids) and other small, soluble molecules like toxins. [“Soluble” particles are so small that they are suspended in solution and do not precipitate out.] When B-cells function as APCs they bind antigen with the BCR and then internalize and process the antigen before presenting it via MHC-II molecules to T-helper cells. B-cells can only take up the specific antigen that is recognized by their B-cell Receptor (BCR). However, the main function of B-cells is to make antibody. When B-cells function as antibody-producing cells they bind antigen with the BCR which then sends a signal to the B-cell to differentiate into an antibody secreting cell called a PLASMA CELL. o Thus, a plasma cell is a B-cell that can make antibody. A B-cell usually needs help from a T-helper to become a plasma cell. To get this help the B-cell must take up, process and present exogenous antigen to the Th-cell. o The antibody the B-cell makes is identical to the membrane-bound antibody making up the BCR and is specific for the antigen that triggered the signaling for differentiation into a plasma cell… more on this later. 9  The antibody the plasma cells makes Is identical to the Antibody bound to the B-cell (BCR) that gave rise to the plasma cell 2. 1. B-lymphocyte binds Ag via its BCR: 1. Processes and presents antigen to T-helper cells via MHC-II molecule 2. Differentiates into a plasma cell that makes antibody 10  ANTIGEN PR CE ING AN PRE ENTATI N of endo enous anti en B H T IN ECTE CE AN H T TU R CE. ia HC I to CT s antigen Non professional Host infected cells tumor cells HC I molecules Important in anti en presentation CT s c toto ic T cells) Cells End result is End result is acti atedCT s Anti od and Cell mediated Immunit production A ilit to ills infected cells Humoral and Tumor cells. Immunit Remember: any host cell that has a nucleus and either gets invested (intracellular microbe) or becomes a tumor cell, can process and present ENDOGENOUS ANTIGEN (foreign molecular structures made inside that host cell) via host cell MHC-I molecules to host CTLs (cytotoxic T-lymphocytes). The CTL that has a TCR specific for what ever antigen the host cell is presenting can now bind to the antigen and MHC molecule and become activated. After full activation, the CTL can now target and kill the infected cell. NOTE: Dendritic cells, macrophages and B-lymphocytes have nuclei. Thus, if thse cells become infected (intracellular microbes making endogenous antigen), then they can process and present endogenous antigen via MHC-I to CTLS… just like any other host cell with a nucleus. 11 Practice Questions: Short answer questions: 1. A. Do Dendritic cells, Macrophages and B-lymphocytes have nuclei? a) Yes b) No B. Can Dendritic cells, Macrophages and B-lymphocytes get infected or become tumor cells? a. Yes b. No C. Can Dendritic cells, Macrophages and B-lymphocytes present endogenous antigen to CTLs??? a. Yes b. No EXPLAIN … co ered in class and ill also co er in Zoom office our 2. W at is t e ad anta e to t e ost to a in t e t o pat a s for anti en processin and presentation? 3. A B-lymphocyte becomes infected with the Bovine Leukemia virus (BLV). Some of the virally-infected B-cells are killed by NK cells and viral proteins enter the extracellular space. What can the Adaptive immune system do in response to this infection? Check all that apply: a. Infected B-cells can process and present multiple different endogenous viral antigens to CTLs that have the appropriate TCR.. b. B-cells can bind exogenous BLV viral protein epitopes that are specifically recognized by their unique BCR, internalize that specific viral antigen, process it and present it to T-helper cells. The T-helper cell must have a TCR that recognizes the specific antigen the B-cell is presenting. c. B-cells that present exogenous BLV viral antigens to T-helper cells and receive help from them become plasma cells and make antibody that recognizes the same antigen/epitope as their BCR recognized and internalized in the first place. d. CTLs that have TCRs that recognize BLV antigens presented to them by the infected B-cells become activated, receive help from T-helper cells and now can kill the BLV-infected B-lymphocytes. ANSWERS ON NEXT PAGE. During Zoom office hours we will discuss why the correct answer was the best choice and why the other options were not. 12 1. Yes to all of these. 2. Short answer question Exogenous pathway: Extracellular pathogens make exogenous antigen that in the end results in activation of T-helper cells… Some T-helper cells will provide signals to B-cells to make antibody… The main response of the exogenous pathway is antibody production (adaptive humoral immune response). (Some T- helper cells will also help the CTLs. Antibody is what can target extracellular pathogens Endogenous pathway: Infected host cells (and host tumor cells) process and present endogenous antigen that in the end results in primarily a Cell-Mediated Immune (CMI) response with activation of CTLs (Cytotoxic T-lymphocytes). These activated, antigen-specific CTLs can now kill the host infected or host tumor cells. 3. All of these things can occur. 13