T-Cell_Mediated_Immunity2023_Ingrid Herrmann.pptx

T-Cells: Cell- Mediated Immunity ILA by Dr. Herrmann 1 Objectives • Let's refresh some of the objectives from the adaptive immunity lecture (from Exam 3) and build on them: • Recall the main functions of cell mediated immunity including the immune cells that play a role • Recall costimulators/coi...

T-Cells: Cell- Mediated Immunity ILA by Dr. Herrmann 1 Objectives • Let's refresh some of the objectives from the adaptive immunity lecture (from Exam 3) and build on them: • Recall the main functions of cell mediated immunity including the immune cells that play a role • Recall costimulators/coinhibitors for T-cell activation including a few new ones such as ICOS and PD-1 (see slides 18) • Recall the functions and activation of CD 8 positive T cells • List the effector T cells and recognize their defining cytokines • Describe the functions of the T cells within the immune system for example what kind of m/o’s do they help eliminate? (slide 25 makes a good go-to) • Analyze Clinical Correlates for example and how these relate to the cells/costimulators/coinhibitors we have discussed in this lecture Cell-mediated immunity • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes. • A major role for T lymphocytes is in cell-mediated immunity: • which provides defense against infections by microbes that live and reproduce inside host cells. • In all viral and some bacterial, fungal, and protozoan infections, microbes may find a haven inside cells, • from where they must be eliminated by cell-mediated Cell-mediated immunity • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes. • A major role for T lymphocytes is in cell-mediated immunity: • which provides defense against infections by microbes that live and reproduce inside host cells. • In all viral and some bacterial, fungal, and protozoan infections, microbes may find a haven inside cells, • from where they must be eliminated by cell-mediated Why do T cells stimulate macrophages? • Many microbes are ingested by phagocytes as part of the early defense mechanisms of innate immunity • These microbes are killed by microbicidal mechanisms that are largely limited to phagocytic vesicles (to protect the cells themselves from damage by these mechanisms). • However, some of these microbes have evolved to resist the microbicidal activities of phagocytes and are able to survive, and even replicate, in the vesicles of phagocytes! • In such infections, T cells stimulate the ability of macrophages to kill the ingested microbes. How can T cells help with extracellular microbes? • Some extracellular microbes, such as some bacteria and fungi, are readily destroyed if they are phagocytosed, especially by neutrophils. • Notice that bacteria and fungi can be extracellular or intracellular depending on the genus and species (see examples on slide 7) • Other extracellular pathogens, such as helminthic parasites, are destroyed by special types of leukocytes (eosinophils). • In these infections, T cells provide defense by recruiting T cells destroying non-phagocytic cells such as epithelial cells • Some microbes, notably viruses, are able to infect and replicate inside a wide variety of cells, and parts of the life cycles of the viruses take place in the cytosol and nucleus. • These infected cells often do not possess intrinsic mechanisms for destroying the microbes, especially outside vesicles. • Even some phagocytosed microbes within macrophages can escape into the cytosol and evade the microbicidal mechanisms of the vesicular compartment. • T cells kill the infected cells, thus eliminating the reservoir of infection (see next slide, letter B) Types of intracellular microbes combated by T cell–mediated immunity. A, Microbes may be ingested by phagocytes and may survive within vesicles (phagolysosomes) or escape into the cytosol, where they are not susceptible to the microbicidal mechanisms of the phagocytes. B, Viruses may infect many cell types, including nonphagocytic cells, and replicate in the nucleus and cytosol of the infected cells. Rickettsiae and some protozoa are obligate intracellular parasites that reside in nonphagocytic cells. Don’t forget other roles of T-cells • Other populations of T cells help B cells to produce antibodies as part of humoral immune responses (talked about in next ILA) • Some T cells, especially CD8 cells + T cells, also destroy cancerous • Notice in previous slide (Letter B) the function of CD8 + T cells in killing infected cells • Notice also on previous slide the Th17 subset using neutrophils for recruitment and activation to be used against extracellular m/o’s (the one time you hear about a T cell working against extracellular m/o’s) In a Nutshell • Most of the functions of T lymphocytes: • activation of phagocytes (see next slide), • killing of infected and tumor cells (see next slide), • help for B cells • Recall that these require that the T lymphocytes interact with other cells, which may be phagocytes, infected host cells, or B lymphocytes. • Remember that the initiation of T cell responses requires that naive T cells recognize antigens displayed by dendritic cells (antigen presentation), which capture antigens and concentrate them in lymphoid organs. • Thus, T lymphocytes work by communicating with other cells. • Also recall that the specificity of T cells for peptides displayed by major histocompatibility complex (MHC) molecules ensures that the T cells can see and respond only to antigens associated with other host cells Explanation of previous diagram: Induction and effector phases of cell-mediated immunity • Induction of response: Naive CD4 + T cells and CD8 + T cells recognize peptides that are derived from protein antigens and presented by dendritic cells (DCs) in peripheral lymphoid organs. • The T lymphocytes are stimulated to proliferate and differentiate into effector cells, many of which enter the circulation. • Side note: Some of the activated CD4 + T cells remain in the lymph node, migrate into follicles, and help B cells to produce antibodies: Follicular Helper T cells (Tfh) • Migration of effector T cells and other leukocytes to site of antigen: effector T cells and other leukocytes migrate through blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues. • T cell effector functions: CD4 + T cells recruit and activate phagocytes to destroy microbes, and CD8 + cytotoxic T lymphocytes (CTLs) kill infected cells. Remember IL-2 and clonal expansion? Expansion and decline of T cell responses. The numbers of CD4 + and CD8 + T cells specific for various antigens in inbred mice and the clonal expansion and contraction during immune responses are illustrated Remember: the full activation of T cells depends on the recognition of costimulators on APCs in addition to antigen Clinical Correlate: Why do I have to be familiar with these costimulators (handshakes)? • The increasing understanding of costimulators has led to new strategies for inhibiting harmful immune responses. • Agents that block B7:CD28 interactions are used in the treatment of disorders in which T cell activation causes organ dysfunction, such as certain autoimmune diseases and graft rejection • Antibodies that block CD40:CD40L interactions are being tested in these diseases. Inhibitory Receptors of T Cells: CTLA-4 and PD-1 • Inhibitory receptors are critical for limiting and terminating immune responses . • These inhibitory receptors have been called coinhibitors to contrast them with the costimulators discussed earlier. • Two important inhibitory receptors—CTLA-4 and PD-1—are structurally related to CD28. • CTLA-4, like CD28, recognizes B7-1 and B7-2 on APCs (see next slide originally from adaptive immunity lecture) • PD-1 recognizes two different but structurally related ligands, PD-L1 and PD-L2, on many cell types. • Both CTLA-4 and PD-1 are induced in activated T cells, and function to terminate responses of these cells. • CTLA-4 also plays an important role in the suppressive function of regulatory T cells (so this means if you suppress T regs then you are stimulating T cells!)-brain teaser! Clinical Correlate: Why are coinhibitors clinically relevant? • CTLA-4 and PD-1 prevent responses to self antigens • Also involved in inhibiting T cell responses to some tumors and chronic viral infections. • These discoveries are the basis for the use of antibodies that block CTLA-4 or PD-1 to enhance immune responses to tumors in cancer patients • Because the normal function of these inhibitory receptors is to prevent immune responses against self antigens which can result in autoimmune disease. Stimuli for Activation of CD8 Cells + T • The activation of CD8 + T cells is stimulated by recognition of class I MHC–associated peptides and requires costimulation and helper T cells . • CD8 + T cells function in much the same manner to kill infected cells and tumor cells, their responses to microbial antigens and tumor antigens are essentially similar. • However, the responses of CD8 + T cells differ in several ways from responses of CD4 + T lymphocytes (see next slide) Responses of CD8 + T cells differ in several ways from responses of CD4 + T lymphocytes • The initiation of CD8 + T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells • Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). • Remember that all nucleated cells in the body express MHC Class 1 • The differentiation of naive CD8 + T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4 + helper T cells Activation of CD8 + T cells. Antigen-presenting cells (APCs) , principally dendritic cells, may ingest and present microbial antigens to CD8 + T cells (cross-presentation) and to CD4 + helper T cells. Sometimes, the APC may be infected and can directly present antigens (not shown). The helper T cells then produce cytokines that stimulate the expansion and differentiation of the CD8 + T cells. CTLs, Cytotoxic T lymphocytes. Development of effector CD4 + T cells. When naive CD4 + T cells are activated in secondary lymphoid organs, they proliferate and differentiate into effector cells. Some of the effectors (the Th1, Th2, and Th17 populations) mostly exit the lymphoid organ and function to eradicate microbes in peripheral tissues. Other differentiated cells, called follicular helper T (Tfh) cells, remain in the lymphoid organ and help B cells to produce potent antibodies. Subsets of CD4 + Helper T Cells Distinguished by Cytokine Profiles • CD4 + helper T cells may differentiate into three subsets of effector cells that produce distinct sets of cytokines that function to defend against different types of microbial infections in tissues, and a fourth subset that activates B cells in secondary lymphoid organs (remember this one from previous slide?) • See next slide (Slide 25) for helper T cell subsets and distinct cytokines and yes you need to know this next slide for boards! • Notice from the chart that these effector T cells can also help with extracellular pathogens as well!-brain teaser since T cells normally help with intracellular pathogens Subsets of CD + T cells • Each subset of CD4 + T cells develops in response to the types of microbes that subset is best at eradicating. • Notice from previous charts that different microbes elicit the production of different cytokines from dendritic cells and other cells • Think about what is the body dealing with at that time? What kind of microbe? • And then you will have the appropriate subset of CD+ T cell in response Th1 • The Th1 subset is induced by microbes that are ingested by and activate phagocytes, primarily macrophages • Th1 cells stimulate phagocyte-mediated killing of ingested microbes • The signature cytokine of Th1 cells is interferon-γ (IFN-γ), the most potent macrophage-activating cytokine known (See next slide for image) • Th1 cells, acting through CD40 ligand and IFN- γ , increase the ability of macrophages to kill phagocytosed microbes (see slide 30) Th2 Cells • Th2 cells are induced by parasitic worm infections and promote IgE-, mast cell- and eosinophil-mediated destruction of these parasites • The signature cytokines of Th2 cells—IL-4, IL-5, and IL-13— function cooperatively in eradicating worm infections. • Helminths are too large to be phagocytosed, so mechanisms other than macrophage activation are needed for their destruction. • When Th2 and related Tfh cells encounter the antigens of helminths, the T cells secrete their cytokines. • IL-4 produced by Tfh cells stimulates the production of IgE antibodies, which coat the helminths and thus help in their clearance • See next slide (notice that based on the type of antigen or /m/o that this determines the type of T cell) Th2 cytokines inhibit classical macrophage (M1) activation and stimulate the alternative pathway of macrophage (M2) activation • IL-4 and IL-13 shut down the activation of inflammatory macrophages, thus terminating these potentially damaging reactions. • These cytokines also can activate macrophages (M2) to secrete growth factors that act on fibroblasts to increase collagen synthesis and induce fibrosis. • This type of macrophage response is called alternative macrophage activation, to distinguish it from classical activation which enhances microbicidal functions. Clinical Correlate: What is the alternative pathway of macrophage (M2) activation? • Alternative macrophage activation mediated by Th2 cytokines may play a role in tissue repair following injury and may contribute to fibrosis in a variety of disease states. • See next slide and notice with M 2 activation you get anti-inflammatory effects, wound repair and fibrosis 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. • Allergies are the most common type of immune disorder; we will return to these diseases in when we discuss hypersensitivity reactions. • Antagonists of IL-5 are approved for the treatment of asthma, and an antibody against the IL-4 receptor is approved for the allergic disease atopic dermatitis. Th17 Cells • Th17 cells develop in response to extracellular bacterial and fungal infections and induce inflammatory reactions that destroy these organisms • The major cytokines produced by Th17 cells are IL-17 and IL-22. • This T cell subset was discovered during studies of inflammatory diseases, many years after Th1 and Th2 subsets were described, and its role in host defense was established later. • Th17 cells are critical for defense against fungal and bacterial infections, especially in epithelial barrier tissues. • See next slide Function of Th17 cells • The major function of Th17 cells is to stimulate the recruitment of neutrophils and, to less extent, monocytes, • thus inducing the inflammation that accompanies many T cell–mediated adaptive immune responses. • Recall that inflammation also is one of the principal reactions of innate immunity • Typically, when T cells stimulate inflammation, the reaction is stronger and more prolonged than when it is elicited by innate immune responses only. Function of Th17 cells • IL-17 secreted by Th17 cells stimulates the production of chemokines from other cells, and these chemokines are responsible for leukocyte recruitment. • Th17 cells also stimulate the production of antimicrobial substances, called defensins, that function like locally produced endogenous antibiotics. • IL-22 produced by Th17 cells induces epithelial cell defensin production, helps to maintain the integrity of epithelial barriers and may promote repair of damaged epithelia (as shown in slide 39) Clinical Correlate for Th 17 • Rare individuals who have inherited defects in Th17 responses are prone to developing chronic mucocutaneous candidiasis and bacterial abscesses in the skin. • Th17 cells are also implicated in numerous inflammatory diseases: • antagonists of IL-17 and of the Th17-inducing cytokine IL23 are very effective treatments for psoriasis, an inflammatory skin disease. • An antagonist that neutralizes IL-12 and IL-23 (by binding to a protein shared by these cytokines), and thus inhibits the development of both Th1 and Th17 cells, is used for the treatment of inflammatory bowel disease and psoriasis. Differentiation and Functions of CD8 Lymphocytes + Cytotoxic T • Phagocytes are best at killing microbes that are confined to vesicles • Microbes that directly enter the cytosol (e.g., viruses) or escape from phagosomes into the cytosol (e.g., some ingested bacteria) are relatively resistant to the microbicidal mechanisms of phagocytes • Eradication of such cytosolic pathogens requires another effector mechanism of T cell–mediated immunity: CD8 + CTLs. • Remember that CTLs also serve a vital role in defense against cancers • CD8 + T lymphocytes activated by antigen and other signals differentiate into CTLs that are able to kill infected cells expressing the antigen. • See next slide how this works in detail More on CD8+ • CD8 + CTLs recognize class I MHC–peptide complexes on the surface of infected cells and kill these cells, thus eliminating the reservoir of infection. • The T cells recognize MHC-associated peptides by their TCR and the CD8 coreceptor. • These infected cells also are called targets of CTLs, because they are destroyed by the CTLs. T lymphocytes acting as a team • 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. • However, if the microbes are able to escape from vesicles into the cytoplasm, they become insusceptible to the killing mechanisms of activated macrophages, and their elimination requires destruction of the infected cells by CD8 + CTLs. • See next slide for this great teamwork! Clinical Correlate- T cell exhaustion • Some viruses evade elimination and establish chronic infections by stimulating expression of inhibitory receptors, including PD-1 (programmed [cell] death protein 1); on CD8 + T cells, thus inhibiting the effector functions of CTLs. • This phenomenon, in which the T cells mount an initial response against the virus but the response is prematurely terminated, has been called T cell exhaustion • This typically occurs as a reaction to chronic antigenic stimulation, as in chronic viral infections or tumors • In this mechanism, repeatedly stimulated T cell terminates its own response • See next slide and notice PD- 1 and CTLA-4 being stimulated which causes and inhibitory response Clinical Correlate: Tumors • Tumors, like infectious pathogens, have developed several mechanisms for evading or resisting CD8 + T cell–mediated immunity. • These mechanisms include inhibiting expression of class I MHC molecules and inducing T cell exhaustion. • Blocking some of these evasion mechanisms provides effective strategies for unleashing antitumor immunity Review Questions • 1. What are the types of T lymphocyte–mediated immune reactions that eliminate microbes that are sequestered in the vesicles of phagocytes and microbes that live in the cytoplasm (cytosol) of infected host cells? • 2. What are the major subsets of CD4 + effector T cells, how do they differ, and what are their roles in defense against different types of infectious pathogens? Can you recognize some of the cytokines that play a role? • 3. What are the mechanisms by which T cells activate macrophages, and what are the responses of macrophages that result in the killing of ingested microbes? • 4. How do CD8 + CTLs kill cells infected with viruses? Also describe how CD4+ cells play a role with this as well • 5. Can you explain what is going on with each of the pictures I have shared in this PPT? Try explaining these pictures out loud to yourself OR to a study buddy.