Lecture 15 - Immunology Studyguide PDF

Manipulation of the B7/CD28 interaction for therapeutic purposes => Intervention to block T cell activation Normal signaling Recombinant “drug” CTLA-4 approved for RA and tissue transplant Certainly! Let's break down the manipulation of the B7/CD28 interaction for therapeutic purposes and how it can...

Manipulation of the B7/CD28 interaction for therapeutic purposes => Intervention to block T cell activation Normal signaling Recombinant “drug” CTLA-4 approved for RA and tissue transplant Certainly! Let's break down the manipulation of the B7/CD28 interaction for therapeutic purposes and how it can be used to intervene in T cell activation. 1.Normal Signaling: 1. In normal circumstances, T cell activation occurs when the T cell receptor (TCR) recognizes an antigen presented by an antigen-presenting cell (APC). However, for full activation, a second signal is required, which is provided by the interaction between the CD28 receptor on the T cell and its ligands, B7-1 (CD80) and B7-2 (CD86) on the APC. 2.Intervention to Block T Cell Activation: 1. The goal of therapeutic intervention is to block the CD28 co-stimulatory pathway, thereby preventing T cell activation, which is crucial in various immune-related disorders like autoimmune diseases or transplant rejection. 3.Costimulatory Blockade: 1. One approach to achieve this is through costimulatory blockade. By inhibiting the CD28 pathway, T cell activation can be suppressed, leading to reduced inflammation and tissue damage in autoimmune 1 diseases or decreased rejection of transplanted organs. 4. CTLA-4 as a Target: 1. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a molecule that competes with CD28 for binding to B7-1 and B7-2. It acts as an inhibitory molecule and dampens T cell activation. By targeting CTLA-4, we can enhance T cell activation and potentially strengthen the immune response against pathogens or cancer cells. 5.Use of Recombinant Drugs: 1. Recombinant drugs can be designed to block the binding site of CD28, preventing its interaction with B7-1 and B7-2. This blockade inhibits the co-stimulatory signal required for full T cell activation. 6.Clinical Applications: 1. CTLA-4 blockade has been approved for certain autoimmune diseases like rheumatoid arthritis (RA) and for preventing rejection in tissue transplantation. By blocking CTLA-4, the immune system is activated, leading to enhanced T cell responses against the target antigens. 7.Suppressing Immune System: 1. In the context of autoimmune diseases, suppressing the immune system can alleviate symptoms by reducing the activity of autoreactive T cells that mistakenly attack healthy tissues. 8.Blocking Inhibitory Signals: 1. Conversely, blocking inhibitory signals like CTLA-4 can activate the immune system, which can be beneficial in cancer immunotherapy. By enhancing T cell activation and proliferation, the immune system can better target and eliminate cancer cells. In summary, manipulation of the B7/CD28 interaction for therapeutic purposes involves inhibiting the co-stimulatory signal required for T cell activation. This can be achieved through costimulatory blockade, with CTLA-4 serving as a key target. Recombinant drugs can be designed to block CD28 or inhibit inhibitory molecules like CTLA-4, depending on the desired therapeutic outcome, whether it's suppressing the immune system in autoimmune diseases or activating it in cancer immunotherapy. 1 Functions of CD4+ helper T cells Through cytokine production, CD4+ helper T cells serve critical roles in: 1. phagocyte-mediated elimination of microbes (Th1) 2. activation of eosinophils (Th2) and neutrophils (Th17) 3. stimulation of antibody production by B cells (Tfh) ChatGPT ChatGPT CD4+ helper T cells, also known as T helper cells, play crucial roles in orchestrating immune responses by producing cytokines that regulate various aspects of the immune system. Here's a detailed explanation of their functions, particularly focusing on Th1 and Th17 subsets: 1.Th1 Cells: 1. Function: Th1 cells primarily regulate cellular immunity and the phagocyte-mediated elimination of intracellular pathogens, such as bacteria and viruses. 2. Cytokines Produced: Th1 cells produce cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2). 3. Role in Adaptive and Innate Immunity: Th1 cells coordinate adaptive and innate immune responses. They activate macrophages and dendritic cells, enhancing their microbicidal activities. This activation leads to increased phagocytosis, production of reactive oxygen species (ROS), and presentation of 2 antigens to other immune cells. 2. Th17 Cells: 1. Function: Th17 cells are involved in inflammatory responses and host defense against extracellular pathogens, particularly fungi and bacteria at mucosal surfaces. 2. Cytokines Produced: Th17 cells produce interleukin-17 (IL-17), IL-21, and IL-22. 3. Activation of Neutrophils: Th17 cells stimulate the recruitment and activation of neutrophils, which are crucial for eliminating extracellular pathogens. 4. Coordinated Response: Th17 cells contribute to the coordination of adaptive and innate immune responses at mucosal sites. They promote the production of antimicrobial peptides and the maintenance of mucosal barrier integrity. Both Th1 and Th17 subsets play critical roles in coordinating adaptive and innate immune responses against different types of pathogens. While Th1 cells primarily target intracellular pathogens and activate phagocytes, Th17 cells focus on defense against extracellular pathogens, particularly at mucosal surfaces, and activate neutrophils and epithelial cells. Their coordinated actions help ensure effective immune responses tailored to the nature of the invading pathogens. 2 Steps in the T helper (Th) cell immune response The steps in the T helper (Th) cell immune response involve a series of events starting from the activation of naive CD4+ T cells to the execution of effector functions. Here's a detailed explanation: 1.Naïve CD4+ T Cell Activation: 1. Naïve CD4+ T cells circulate in the bloodstream and lymphoid organs, such as lymph nodes and spleen, in an inactive state. When an antigen-presenting cell (APC), such as a dendritic cell, presents an antigen to a naive CD4+ T cell via the major histocompatibility complex class II (MHC-II) molecules, along with co-stimulatory signals, the T cell becomes activated. 2.Antigen Recognition and Induction of Responses in Lymphoid Organs: 1. Upon antigen recognition, the naive CD4+ T cell undergoes clonal expansion and differentiation in secondary lymphoid organs, such as lymph nodes. This process is crucial for generating a pool of antigen-specific effector T cells. 3.T Cell Proliferation and Differentiation: 1. Activated CD4+ T cells undergo proliferation and differentiation into effector T cells with distinct functions. The cytokine milieu present during activation influences the differentiation fate of CD4+ T 3 cells. For example, interleukin-12 (IL-12) promotes Th1 differentiation, IL-4 promotes Th2 differentiation, and IL-6 and transforming growth factor-beta (TGF-β) promote Th17 differentiation. 4. Differentiated CD4+ Th Cells Enter Circulation: 1. Once differentiated, CD4+ Th cells enter the circulation to migrate to sites of inflammation or infection. 5.Migration of Effector Cells and Other Leukocytes to Site of Antigen: 1. Effector CD4+ Th cells migrate to the site of antigenic challenge, guided by chemokines and adhesion molecules. At the site of infection or inflammation, they interact with other immune cells, such as macrophages, neutrophils, and B cells. 6.Effector Functions of T Cells: 1. CD4+ Th cells execute their effector functions, which include: 1. Inducing inflammation: Th cells release cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which activate macrophages and promote inflammation. 2. Activating leukocytes: Th cells stimulate the activation and recruitment of other leukocytes, such as neutrophils and eosinophils, to the site of infection or inflammation. 3. Coordinating adaptive immune responses: Th cells help B cells produce antibodies (Th2 cells) or provide help to CD8+ cytotoxic T cells (Th1 cells). 4. Mediating delayed-type hypersensitivity (DTH) reactions: Th1 cells can cause tissue damage in delayedtype hypersensitivity reactions, which occur when activated T cells encounter antigen in tissues and initiate an inflammatory response. 7.Persistence of T Follicular Helper (Tfh) Cells: 1. Some activated CD4+ T cells differentiate into T follicular helper (Tfh) cells, which migrate to B cell follicles within secondary lymphoid organs and provide help to B cells for antibody production. Tfh cells play a crucial role in the generation of long-lived antibody responses. In summary, the steps in the T helper cell immune response involve activation, proliferation, differentiation, migration, and execution of effector functions, which collectively contribute to the clearance of pathogens and the regulation of immune responses. However, dysregulated T cell responses can lead to immune-mediated diseases, such as delayed-type hypersensitivity reactions. 3 Development of Th1, Th2, and Th17 subsets Differentiation of each subset is induced by the types of microbes each subset is best able to combat Which subset develops is due to the response to cytokines generated early in immune response Cytokines that drive development of Th cell subsets are produced by APCs Each subset produces cytokines that promote own development and suppress development of other subsets Each subset expresses chemokine receptors to detect chemokines produced in responses to certain antigens The development of Th1, Th2, and Th17 subsets of CD4+ T cells is intricately regulated by the types of pathogens encountered, the cytokine milieu present during antigen presentation, and the expression of specific chemokine receptors. Here's a detailed explanation of each point: 1.Differentiation Induced by Microbial Context: 1. The differentiation of each Th subset is influenced by the types of microbes each subset is best equipped to combat. For example, Th1 cells are effective against intracellular pathogens such as viruses and certain bacteria, while Th2 cells are more adept at combating extracellular parasites like helminths. Th17 cells, on the other hand, play a role in defense against extracellular bacteria and fungi, particularly at mucosal surfaces. 2.Cytokine-Mediated Differentiation: 1. The initial cytokine signals received by naive CD4+ T cells during antigen presentation drive their differentiation into specific Th subsets. For example, IL-12 produced by antigen-presenting cells (APCs) like dendritic cells promotes Th1 differentiation, while IL-4 promotes Th2 differentiation and IL-6 and TGF-β promote Th17 differentiation. 4 3. Cytokine Production by APCs: 1. Antigen-presenting cells, such as dendritic cells and macrophages, produce the cytokines necessary for driving Th cell subset differentiation. These APCs sense the presence of specific pathogens or their components and tailor their cytokine production accordingly to direct the adaptive immune response towards the most effective effector pathway. 4.Autocrine and Paracrine Regulation: 1. Once CD4+ T cells commit to a specific Th subset, they produce cytokines that not only promote their own development (autocrine regulation) but also suppress the development of other subsets (paracrine regulation). For example, Th1 cells produce IFN-γ, which reinforces Th1 differentiation and inhibits Th2 differentiation. 5.Chemokine Receptor Expression: 1. Each Th subset expresses specific chemokine receptors that allow them to migrate to sites of infection or inflammation where their respective pathogens are encountered. For instance, Th1 cells express CXCR3, which responds to chemokines like CXCL9, CXCL10, and CXCL11, guiding Th1 cells to sites of viral or intracellular bacterial infections. Th2 cells express CCR3 and CCR4, enabling them to migrate to sites of allergic inflammation or helminth infections. Th17 cells express CCR6, facilitating their recruitment to mucosal surfaces where they combat extracellular bacteria and fungi. In summary, the development of Th1, Th2, and Th17 subsets of CD4+ T cells is tightly regulated by the microbial context, cytokine signals provided during antigen presentation, APC-derived cytokines, autocrine and paracrine regulation, and expression of specific chemokine receptors. This sophisticated regulatory network ensures that the adaptive immune response is tailored to combat different types of pathogens encountered by the host 4 Each CD4+ effector subset targets specific pathogens Certainly, let's delve into the details of each CD4+ T cell effector subset and their specific roles in immune responses and disease: 1.Th1 Cells: 1. Cytokines Produced: Th1 cells primarily produce interferon-gamma (IFN-γ). 2. Principal Target Cells: Macrophages. 3. Major Immune Reaction: Activation of macrophages. 4. Host Defense: Th1 cells are critical for defense against intracellular pathogens such as viruses, certain bacteria (e.g., Mycobacterium tuberculosis), and protozoa (e.g., Leishmania spp.). They activate macrophages to enhance their microbicidal activities, including phagocytosis and killing of intracellular pathogens. 5. Role in Disease: Th1 cells play a role in autoimmune diseases and chronic inflammation. Excessive Th1 responses can lead to tissue damage and contribute to the pathogenesis of diseases like rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. 2.Th2 Cells: 5 1. 2. 3. 4. Cytokines Produced: Th2 cells produce interleukin-4 (IL-4), IL-5, and IL-13. Principal Target Cells: Eosinophils. Major Immune Reactions: Activation of eosinophils and mast cells, and alternative activation of macrophages. Host Defense: Th2 cells are essential for defense against helminthic parasites. They stimulate the production of antibodies, particularly IgE, which activate mast cells and eosinophils to combat parasitic infections. 5. Role in Disease: Th2 cells are implicated in allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. Dysregulated Th2 responses can lead to excessive inflammation and tissue damage associated with allergic reactions. 1.Th17 Cells: 1. Cytokines Produced: Th17 cells produce interleukin-17 (IL-17) and IL-22. 2. Principal Target Cells: Neutrophils. 3. Major Immune Reactions: Recruitment and activation of neutrophils. 4. Host Defense: Th17 cells play a crucial role in defense against extracellular bacteria and fungi, particularly at mucosal surfaces. They stimulate the production of antimicrobial peptides and enhance barrier function. 5. Role in Disease: Th17 cells are implicated in autoimmune diseases and inflammation. Excessive Th17 responses can contribute to the pathogenesis of diseases such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease by promoting chronic inflammation and tissue damage. In summary, each CD4+ T cell effector subset targets specific pathogens and produces distinct cytokines that orchestrate immune responses tailored to combat different types of infections. However, dysregulated or excessive responses by these subsets can lead to immune-mediated diseases characterized by chronic inflammation and tissue damage. Understanding the roles of Th1, Th2, and Th17 cells is crucial for developing targeted therapeutic interventions for immune-related disorders. 5 Th1 cells activate macrophages to destroy intracellular microbes CD40L = CD40 Ligand; NO = nitric oxide; ROS = reactive oxygen species Certainly, let's delve into the details of how Th1 cells activate macrophages and the subsequent responses of activated macrophages: A. Activation of Macrophages by Th1 Cells: Th1 cells play a crucial role in activating macrophages to enhance their ability to destroy intracellular microbes. This process involves several key interactions: CD40-CD40L Interaction: CD40 ligand (CD40L) expressed on the surface of Th1 cells interacts with CD40 receptors on macrophages. This interaction provides a co-stimulatory signal necessary for macrophage activation. IFN-γ Signaling: Th1 cells produce interferon-gamma (IFN-γ), which binds to IFN-γ receptors on macrophages. This signaling event triggers a series of intracellular pathways that lead to macrophage activation. Recognition of Infected Macrophages: Macrophages that have ingested bacteria or other intracellular pathogens present antigens derived from these microbes on their surface. CD4+ T cells, including Th1 cells, recognize these antigens presented by major histocompatibility complex class II (MHC-II) 6 molecules on the surface of infected macrophages. B. Responses of Activated Macrophages: Once activated by Th1 cells, macrophages exhibit several effector functions aimed at eliminating intracellular microbes: Enhanced Killing of Phagocytosed Bacteria: Activated macrophages increase their capacity to kill phagocytosed bacteria through mechanisms such as the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which have microbicidal properties. Secretion of Inflammatory Cytokines: Activated macrophages secrete pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). These cytokines help recruit other immune cells to the site of infection and promote inflammation, aiding in the clearance of pathogens. Increased Expression of Molecules Required for T Cell Activation: Activated macrophages upregulate the expression of co-stimulatory molecules such as CD80 and CD86, as well as MHC-II molecules. This enhances their ability to present antigens to CD4+ T cells, leading to further activation and amplification of the immune response. C. Amplification of Responses and Potential Damage: While the activation of macrophages by Th1 cells is essential for effective host defense against intracellular pathogens, it is also crucial to tightly regulate the magnitude and duration of this response to prevent excessive tissue damage. Uncontrolled activation of macrophages and sustained production of pro-inflammatory cytokines can lead to tissue damage and contribute to the pathogenesis of inflammatory diseases. In summary, the interaction between Th1 cells and macrophages plays a central role in the immune response against intracellular microbes. Th1 cells activate macrophages through CD40-CD40L interaction and IFN-γ signaling, leading to enhanced microbicidal activity, secretion of inflammatory cytokines, and increased antigen presentation. However, proper regulation of this response is essential to prevent collateral tissue damage and maintain immune homeostasis. 6 Functions of Th2 cells Induced in response to helminth infection (and allergens) IL-4 is the defining cytokine Th2 cells play critical roles in orchestrating immune responses against helminth infections and allergens. Their functions are primarily driven by the cytokine interleukin-4 (IL-4), which is central to the Th2 response. Here's a detailed explanation of the functions of Th2 cells: 1.Induction in Response to Helminth Infection and Allergens: 1. Th2 cells are induced in response to helminth infections (parasitic worms) and exposure to allergens such as pollen, dust mites, and animal dander. 2.IL-4 as the Defining Cytokine: 1. IL-4 is the defining cytokine produced by Th2 cells. It is essential for initiating and driving the Th2 immune response. 3.Antigen Uptake and Presentation by Antigen-Presenting Cells (APCs): 1. Helminth antigens or allergens are taken up by APCs such as dendritic cells. These antigens are then presented to naive CD4+ T cells through the interaction of peptide-MHC-II complexes and T cell receptors. 4.Proliferation and Differentiation to Th2 Cells: 7 1. Upon antigen presentation, naive CD4+ T cells differentiate into Th2 cells under the influence of IL-4. This differentiation process involves the activation of specific transcription factors and epigenetic changes that drive Th2 cell lineage commitment. 1.Th2-Mediated Responses: a. IL-4 Response to B Cells: 1. Th2 cells produce IL-4, which acts on B cells to induce class switching to IgE antibody production. IgE antibodies play a crucial role in allergic responses by binding to mast cells and basophils, sensitizing them to allergens. b. Antibody Production and Mast Cell Degranulation: 2. Upon encountering allergens, IgE-bound mast cells and basophils undergo degranulation, releasing inflammatory mediators such as histamine, leukotrienes, and prostaglandins. This leads to allergic symptoms such as itching, sneezing, and bronchoconstriction. c. IL-5 Response to Eosinophils: 3. Th2 cells also produce IL-5, which stimulates the activation, recruitment, and survival of eosinophils. Eosinophils play a role in combating helminth infections and are implicated in allergic inflammation. d. IL-4 and IL-13 Effects on Intestinal Mucus Secretion and Peristalsis: 4. IL-4 and IL-13 contribute to the production of mucus in the intestinal mucosa, aiding in the expulsion of helminths. These cytokines also regulate intestinal peristalsis, promoting the clearance of parasites. In summary, Th2 cells play a crucial role in immune responses against helminth infections and allergens. Their functions are mediated by the production of IL-4, which drives B cell class switching to IgE, eosinophil activation, and modulation of mucosal immunity. However, dysregulated Th2 responses can lead to allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. 7 Functions of Th2 cells Induced in response to helminth infection (and allergens) IL-4 is the defining cytokine Certainly! Th2 cells are a subset of CD4+ T cells that play crucial roles in orchestrating immune responses against helminth infections and allergens. Their functions are primarily driven by the cytokine interleukin-4 (IL-4), which is central to the Th2 immune response. Here's a detailed explanation of the functions of Th2 cells: 1.Induction in Response to Helminth Infection and Allergens: 1. Th2 cells are induced in response to helminth infections, which are parasitic worms that invade host tissues, and exposure to allergens, such as pollen, dust mites, and animal dander. 2.IL-4 as the Defining Cytokine: 1. IL-4 is the defining cytokine produced by Th2 cells. It plays a crucial role in initiating and driving the Th2 immune response. 3.IL-4 Stimulates B Cells to Produce IgE Antibodies: 1. One of the primary functions of IL-4 is to stimulate B cells to undergo class switching to IgE antibody production. IgE antibodies are the predominant antibody isotype produced in response to helminth infections and allergens. IgE antibodies bind to high-affinity receptors (FcεRI) on the surface of mast cells and basophils, sensitizing them to allergens. 8 4. IL-4 and IL-13 Recruitment of Eosinophils: 1. Both IL-4 and IL-13 play roles in recruiting eosinophils, which are specialized white blood cells involved in the immune response against helminth infections and allergic reactions. 2. IL-4 and IL-13 induce the production of chemokines and adhesion molecules that facilitate the recruitment of eosinophils to sites of inflammation or tissue damage. 5.IL-5 Activation of Eosinophils: 1. IL-5, another cytokine produced by Th2 cells, specifically activates eosinophils. IL-5 promotes the survival, activation, and recruitment of eosinophils to sites of inflammation. 2. Activated eosinophils release cytotoxic granule proteins and reactive oxygen species, which contribute to the defense against helminths and the pathogenesis of allergic diseases. In summary, Th2 cells play a crucial role in immune responses against helminth infections and allergens by producing IL-4, which stimulates B cells to produce IgE antibodies and recruits eosinophils to sites of inflammation. IL-5 further activates eosinophils, enhancing their effector functions. This coordinated immune response has evolved to combat worm infections and protect the host from allergens, but dysregulated Th2 responses can lead to allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. 8 Functions of Th17 cells Promote destruction of extracellular bacteria and fungi 9