Effector T Cells Notes.pdf

3/17/22 The Immune System Dr. Dalia Zakaria 1 Adaptive Immunity VI Effector Mechanisms of the Adaptive Immune Responses Effector Mechanisms of T Cells Textbook Reading: Chapter 6 2 1 3/17/22 What Do You Need to Learn? Components of the immune system (an overview) Components of the innate immune syst...

3/17/22 The Immune System Dr. Dalia Zakaria 1 Adaptive Immunity VI Effector Mechanisms of the Adaptive Immune Responses Effector Mechanisms of T Cells Textbook Reading: Chapter 6 2 1 3/17/22 What Do You Need to Learn? Components of the immune system (an overview) Components of the innate immune system Mechanisms of innate immune responses Transition from innate to adaptive immune response Components of the adaptive immune system (lymphocytes and lymphatic system) How do lymphocytes recognize their specific antigens (development) and how do they distinguish between self and non-self molecules (maturation) Mechanisms of lymphocytes activation Effector mechanisms of the adaptive immune responses 3 Objectives After completing this module, you should understand the following: The role of CD8+ cytotoxic T cells in cell mediated immunity The types of activated CD4+ helper T cells and their functions The role of Th1 in enhancing phagocytosis The difference between the M1 and M2 pathways of macrophages and the role of Th1 and Th2 in inducing one of the pathways The importance of the balance between the Th1 and Th2 pathways in order to trigger the appropriate immune response depending on the type of pathogen The function of the Th17 cells The development and signature cytokines for each type of helper T cells The killing mechanisms of the cytotoxic CD8+ T cells including the cooperation with the CD4+ cells 4 2 3/17/22 Differentiation of Activated T Cells CD8+ T cells CD4+ T cells Memory T helper cells Effector T helper cells Th1 Th2 Effector cytotoxic T cells Memory cytotoxic T cells Th17 5 Differentiation of Activated T Cells CD8+ T cells CD4+ T cells Effector T helper cells Th1 Th2 Memory T helper cells Memory Effector cytotoxic T cytotoxic T cells cells Th17 6 3 3/17/22 Activated T Cells Migrate to the Site of Infection Antigen recognition at the site of infection is required to initiate the effector function Costimulation through CD28-B7 binding is not essential for this step 7 Role of Effector T Cells in the Elimination of Microbes CD4+ helper T cells Humoral and cell mediated immunity CD8+ CTL Cell mediated immunity 8 4 3/17/22 Role of T Cells in Cell Mediated Immunity T cells play two main rules: 1. Stimulate the ability of macrophages to kill ingested microbes: Sometimes phagocytes fail to kill ingested microbes. Many pathogenic intracellular bacteria and protozoa are able to survive, and even replicate, in the vesicles of phagocytes 2. kill the infected cells, thus eliminating the reservoir of infection: Viruses and some bacteria, are able to infect and replicate inside a wide variety of cells which often do not possess intrinsic mechanisms for destroying the microbes 9 Role of T Cells in Cell Mediated Immunity 10 5 3/17/22 Development and Functions of CD4+ Helper T Cells (Cytokines Profile) Different microbes elicit the production of different cytokines from dendritic cells and other cells which drive the differentiation of antigen-activated T cells to one or another subset CD4+ helper T cells may differentiate into three major subsets of effector cells (Th1, Th2 and Th17) that produce distinct sets of cytokines that perform different functions in host defense Many activated CD4+ T cells may produce various mixtures of cytokines and cannot be classified into these subsets, and there may be considerable plasticity in these populations so that one subset may convert into another under some conditions 11 Development and Function of Th1 Cells The differentiation of CD4+ T cells to Th1 effector cells is induced by both IL-12 and IFN-γ produced by macrophages (and DCs) and NK cells respectively These together with type I IFNs, produced in response to viral infections, promote Th1 differentiation by activating certain transcription factors IFN-γ promotes Th1 development and inhibits the development of Th2 and Th17 cells in addition to its role in macrophages activation The signature cytokine of Th1 cells is IFN-γ, the most potent macrophage-activating cytokine known 12 6 3/17/22 Th1 Cells CD4+ APC + IL-12 and IFN-γ Development cytokines produced by APCs and NK cells respectively Differentiation to Th1 Migration to the site of infection Interaction with macrophages at the site of infection (antigen presentation and CD40L-CD40 interaction) Production of IFN-γ Signature cytokine Activation of macrophages (classical pathway) 13 Mechanism of Action of Th1 to Enhance Phagocytosis Macrophages ingest and attempt to destroy microbes as part of the innate immune response When microbes are ingested into phagosomes of the macrophages, microbial peptides are presented on class II MHC molecules and are recognized by CD4+ T cells Th1 cells express CD40L and secrete IFN-γ Binding of CD40L to CD40 on macrophages together with IFN-γ binding to its receptor on the same macrophages lead to the synthesis of ROS and NO required to kill ingested microbes (classical macrophage activation) Classically activated macrophages (M1 macrophage) secrete cytokines that stimulate inflammation and have increased expression of MHC and costimulators, which amplify the T cell response 14 7 3/17/22 Th1 Cells 15 Development and Function of Th2 Cells Differentiation of naive CD4+ T cells to Th2 cells is stimulated by IL-4, (produced by mast cells, other tissue cells, and T cells themselves at sites of helminth infection) Activated T cells produce more IL-4 and thus further amplify the Th2 response The signature cytokines of Th2 cells (IL-4, IL-5, and IL-13) function cooperatively in eradicating worm infections which are too large to be phagocytosed IL-4 produced by Tfh cells stimulates the production of IgE antibodies, which coat the helminths. Eosinophils use their Fc receptors to bind to IgE and are activated by IL-5 produced by the Th2 cells, as well as by signals from Fc receptors 16 8 3/17/22 Development and Function of Th2 Cells Activated eosinophils release their granule contents, which are toxic to the parasites IL-13 stimulates mucus secretion and intestinal peristalsis, increasing the expulsion of parasites from the intestines IgE also coats and activates mast cells and is responsible for the activation of mast cells Th2 cytokines inhibit classical macrophage activation and stimulate the alternative pathway of macrophage activation IL-4 and IL-13 shut down the activation of inflammatory macrophages, thus terminating these potentially damaging reactions This type of macrophage response is called alternative macrophage (M2) activation, which impairs the microbicidal functions. These cytokines also can activate macrophages to secrete growth factors that act on fibroblasts to increase collagen synthesis and induce fibrosis 17 Th2 Cells Development cytokine produced by different types of cells including mast cells and activated Th2 cells CD4+ APC + IL-4 In the lymph node, IL-4 induces isotype class switching to IgE Differentiation to Th2 Migration to the site of infection IL-5 Activation of eosinophils IL-4 and IL-13 Peristalsis Signature cytokines Alternative macrophage activation (enhanced fibrosis and tissue repair) IgE bind to their Fc receptors on eosinophils IgE coat mast cells Eosinophils degranulation and killing of the parasite Mast cell degranulation 18 9 3/17/22 Th2 Cells Differentiation to Th2 is induced by IL-4 produced by different types of cells Role of Th2 in allergy will be discussed later 19 Pathways of Macrophages Activation Classical pathway (M1) Induced by: Innate immune signals such as TLR Cytokines such as IFN-γ (could be produced in both innate (NK cells) or adaptive (T cells) immune responses Leads to destruction of microbes and inflammation Alternative pathway (M2) Induced by: IL-4 and IL-13 cytokines Occur in absence of strong TLR signal Leads to tissue repair and termination of inflammation 20 10 3/17/22 Role of Th2 Cells in Allergy Th2 cells are involved in allergic reactions to environmental antigens The antigens that elicit such reactions are called allergens. They induce Th2 responses in genetically susceptible individuals, and repeat exposure to the allergens triggers mast cell and eosinophil activation Antagonists of IL-13 are effective in the treatment of patients with severe asthma who have strong Th2 responses, and agents that block IL-4 receptors or the cytokine IL-5 are being tested in asthma and other allergic disorders 21 Balance between Th1 and Th2 Activation Mycobacterium leprae (bacterium) that causes leprosy, lives inside macrophages and may be eliminated by cell-mediated immune mechanisms If pathogen is not eradicated due to a defect in Th1 cell activation, it will progress to a destructive form of the infection, called lepromatous leprosy A strong cell-mediated immune responses with activated T cells and macrophages around the infection site and few surviving microbes will lead to less injurious infection is called tuberculoid leprosy Leishmania major (protozoal parasite) lives inside macrophages, and its elimination requires the activation of the macrophages by L. major–specific Th1 cells In general, domination of Th2 cells will antagonize Th1 cell mediated immune mechanisms to eradicate the intracellular infection 22 11 3/17/22 Balance between Th1 and Th2 Activation 23 Cutaneous Leishmania Leishmania sp. (protozoal parasite) lives inside macrophages, and its elimination requires the activation of the macrophages by L. major–specific Th1 cells 24 12 3/17/22 Development and Function of Th17 Cells Recognition of fungal glycans and bacterial peptidoglycans and lipopeptides by PRRs on DCs stimulates the secretion of several cytokines, notably IL-1, IL-6, IL-23 and TGF-β These act in concert to activate certain transcription factors which induce Th17 differentiation Interestingly, TGF-β is a powerful inhibitor of immune responses, but when present with IL-6 or IL1, it promotes the development of Th17 cells Th17 cells develop in bacterial and fungal infections and induce inflammatory reactions and production of local antibiotics (defensins) that destroy extracellular microbes and may contribute to several inflammatory diseases The major cytokines produced by Th17 cells are IL-17 and IL-22 Th17 was discovered many years after Th1 and Th2 subsets were described 25 Function of Th17 Cells The major function of Th17 cells is to stimulate the recruitment of neutrophils and, to a lesser extent, monocytes, by secreting IL-17 which stimulate chemokines production Inflammation in this case is stronger and more prolonged than when it is elicited by innate immune responses only Th17 cells also stimulate the production of antimicrobial substances, called defensins, that function like locally produced endogenous antibiotics IL-22 produced by Th17 cells helps to maintain the integrity of epithelial barriers and may promote repair of damaged epithelia An antagonist that neutralizes IL-12 and IL-23 (by binding to a protein shared by these two-chain cytokines), and thus inhibits the development of both Th1 and Th17 cells, is used for the treatment of inflammatory bowel disease and psoriasis 26 13 3/17/22 Th17 Cells CD4+ APC + IL-1, IL-6, IL-23 and TGF-β Development cytokines produced by APCs Differentiation to Th17 Migration to the site of infection IL-17 Recruitment of neutrophils and monocytes Production of antimicrobial peptides by epithelia IL-22 Signature cytokines Increased epithelial barrier integrity Chemokines, TNF, IL-1, Il-6 Inflammation and neutrophil response 27 Th17 Cells Induced by IL-1, IL-6, IL-23 and TGF-β secreted by APCs 28 14 3/17/22 Development of Th1, Th2 and Th17 Cell Subsets Different transcription factors are activated during differentiation For your reference only 29 Functions of Th1, Th2 and Th17 Cell Subsets (Cytokines Profile) 30 15 3/17/22 Th1, Th2 and Th17 Cell Subsets T helper Cell Subset Development Cytokines Signature Cytokines Th1 IFN-γ IL-12 IFN-γ Th2 IL-4 IL-4 IL-5 IL-13 Th17 IL-1 IL-6 IL-23 TGF-β IL-17 IL-22 31 Mechanism of Cytotoxic CD8+ T Cells Killing CTLs do not require costimulation or T cell help for activation, they can be activated by and are able to kill any infected cell in any tissue CTLs kill target cells mainly as a result of delivery of granule proteins into the target cells (exocytosis) Two types of granule proteins critical for killing are granzymes (granule enzymes) and perforin Granzyme B which induce apoptosis (by activating caspases) and perforin which disrupts the integrity of the target cell plasma membrane and endosomal membranes, thereby facilitating the delivery of granzymes into the cytosol and initiate apoptosis 32 16 3/17/22 Mechanism of Cytotoxic CD8+ T Cells Killing Activated CTLs also express a membrane protein called Fas ligand, which binds to a deathinducing receptor, called Fas (CD95), on target cells Engagement of Fas activates caspases and induces target cell apoptosis (this pathway does not require granule exocytosis) Cells that have undergone apoptosis are rapidly phagocytosed and eliminated The mechanisms that induce fragmentation of target cell DNA, which is the hallmark of apoptosis, also may break down the DNA of microbes living inside the infected cells Each CTL can kill a target cell, detach, and go on to kill additional targets 33 Mechanism of Cytotoxic CD8+ T Cells Killing CTLs express Fas ligand membrane protein which binds to a deathinducing receptor, called Fas (CD95), on target cells Granzyme B induces apoptosis by activating caspases Perforin disrupts the integrity of the target cell plasma membrane to facilitate delivery of granzymes into the cytosol Engagement of Fas activates caspases and induces target cell apoptosis (no granule exocytosis) Cells that have undergone apoptosis are rapidly phagocytosed and eliminated Using two types of granule proteins critical for killing are granzymes (granule enzymes) and perforin 34 17 3/17/22 Mechanism of Cytotoxic CD8+ T Cells Killing 35 Cooperation of CD4+ and CD8+ Effector T Lymphocytes CD4+ T cells and CD8+ T lymphocytes may function cooperatively to destroy intracellular microbes If microbes are phagocytosed and remain sequestered in macrophage vesicles, CD4+ T cells may be adequate to eradicate these infections by secreting IFN-γ and activating the microbicidal mechanisms of the macrophages CD8+ T cells also secrete IFN-γ and may contribute to macrophage activation and killing of ingested microbes If the microbes escape from vesicles into the cytoplasm, they become insusceptible to T cell– mediated macrophage activation, and their elimination requires killing of the infected cells by CD8+ CTLs 36 18 3/17/22 Cooperation of CD4+ and CD8+ Effector T Lymphocytes 37 For your reference only 38 19