Cells Of The Immune System PDF

CELLS OF THE IMMUNE SYSTEM Presented by Dr Eman M. Hardudi MD, PhD in immunology Department of microbiology/Faculty of medicine University of Benghazi 1  OBJECTIVES 1. Identify the primary and secondary l...

CELLS OF THE IMMUNE SYSTEM Presented by Dr Eman M. Hardudi MD, PhD in immunology Department of microbiology/Faculty of medicine University of Benghazi 1  OBJECTIVES 1. Identify the primary and secondary lymphoid organs. 2. Enumerate common cells that contribute to natural immunity. 3. Identify the phagocytes cells and their functions as a critical part of the immune response. 4. Identify the variable professional antigen presenting cells. 5. Define T cells as a critical part of the adaptive immune system. 6. Enumerates the different types of T cells. 7. Define B cells and their functions. 2  LYMPHOID TISSUES The primary lymphoid organs, also called generative or central lymphoid organs, include the bone marrow and thymus, and are the sites where lymphocytes first express antigen receptors and attain phenotypic and functional maturity B lymphocytes mature partially in the bone marrow; enter the circulation; migrate to the spleen, where they complete their maturation; and then populate secondary lymphoid organs T lymphocytes mature in the thymus, then enter the circulation, and migrate to secondary lymphoid organs 3  LYMPHOID TISSUES Two important functions shared by the generative organs are to provide growth factors and other molecular signals needed for lymphocyte maturation and to present self antigens for selection of maturing lymphocytes Secondary (or peripheral) lymphoid organs, including the lymph nodes, spleen, and components of the mucosal immune system, are where lymphocyte responses to foreign antigens are initiated and develop Once lymphocytes mature in the primary organs, they are released and make their way to secondary organs, which include the spleen, lymph nodes, appendix, tonsils, and other mucosal-associated lymphoid tissue 4  THE THYMUS The thymus is the site of T cell maturation The thymus is a bilobed organ found in the anterior mediastinum The thymus grows until puberty and then undergoes progressive involution. By late adulthood, it is largely adipose tissue with only a small amount of remaining lymphoid tissue The main role of the thymus is to select T cells that are able to recognize self major histocompatibility complex (MHC), known as positive selection, and to destroy T cells that recognize self antigen 5  THE THYMUS The thymus, which has three main areas: 1. The subcapsular zone contains the earliest progenitor T cells 2. The cortex is densely packed with developing T cells undergoing selection 3. The medulla contains fewer, but more mature, T lymphocytes; these have survived the selection processes and are about to be released to the periphery 6  CLINICAL BOX An inherited disorder of T cell immunity caused by failure of development of the thymus is called the DiGeorge syndrome. These patients suffer from T cell deficiency because of a chromosomal deletion that eliminates genes required for thymus development 7  LYMPH NODES Lymph nodes are scattered throughout the body and filter out microbes or damaged tissue Lymph nodes are responsible for the acquired immune response against antigens The cortex contains B cell-rich areas called follicles 8  LYMPH NODES Afferent lymphatics deliver fluid from the tissues to the subcapsular sinus of the lymph node This fluid contains cells that have encountered pathogens and hence is a source of antigens that stimulate the acquired immune system From the subcapsular sinus, the lymph drains into the cortex of the lymph node The B cell follicles are in contact with T cell-rich regions, which facilitate the interactions between these two lymphocytes that are necessary for antibody production Some follicles contain germinal centers; these are areas where B cells proliferate and differentiate after they have encountered 9 antigen  LYMPH NODES Activated B cells mature into plasma cells, which secrete large amounts of antibody, and are located in the medulla of the lymph node Lymphoid fluid leaves the lymph node through the efferent lymphatics In addition, activated B and T cells and antibody molecules leave the lymph nodes and enter the peripheral blood 10  SPLEEN The spleen is an encapsulated organ in the abdominal cavity where opsonized blood cells are removed from the circulation, and in which lymphocytes respond to blood borne antigens The spleen consists of two basic types of tissue: 1. Red pulp, which encompasses most of the splenic tissue, is involved in the degradation of old red blood cells 2. White pulp is scattered throughout the red pulp and this is where the acquired immune response is initiated 11  SPLEEN The white pulp is organized around central arterioles, which deliver blood (containing lymphocytes and antigen) Like the lymph node, the white pulp of the spleen is organized into T cell-rich regions (periarteriolar lymphoid sheath) and B cell-rich areas (follicles) Antigenic stimulation induces B cell proliferation and the formation of germinal centers 12  MUCOSAL ASSOCIATED LYMPHOID TISSUE(MALT) "MALT" refers to a diffuse collection of lymphoid tissues that line the respiratory, gastrointestinal, and genitourinary tracts MALT produce the immune responses against pathogens that invade the mucosa that line these tracts Like the spleen and lymph nodes, the MALT contains B cell follicles and distinct T cell-rich regions 13  MUCOSAL ASSOCIATED LYMPHOID TISSUE(MALT) Although its organization is similar to the spleen and lymph node, the mucosal immune system is different in several ways: unlike the spleen and lymph node, MALT tissue is not surrounded by a fibrous capsule IgA is the predominant class of immunoglobulin produced in MALT It is not filtering Ag delivered by vessels like the blood vessels or lymphatic vessels An important feature of these epithelial tissues is that they are densely populated with commensal microbes, some of which are essential for normal physiology BALT (Bronchial Associated Lymphoid Tissue), GALT (Gut Associated Lymphoid Tissue), & CALT (Conjunctiva Associated Lymphoid Tissue)are subtypes of MALT 14 CELLS OF THE IMMUNE SYSTEM 15  NEUTROPHILS They are the most abundant population of circulating white blood cells and the principal cell type in acute inflammatory reactions Because of their nuclear morphology, neutrophils are also called polymorphonuclear leukocytes (PMNs) Production of neutrophils is stimulated by granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM- CSF) 16  NEUTROPHILS The main function of neutrophils is to phagocytose microbes, especially opsonized microbes, and necrotic cells products and destroy these in phagolysosomes Additionally, neutrophils may secrete granule contents and also extrude their nuclear contents, forming neutrophil extracellular traps (NETs), which serve to immobilize and kill extracellular microbes but also may damage healthy tissues 17  MONONUCLEAR PHAGOCYTES The mononuclear phagocyte system includes: Circulating bone marrow–derived cells called monocytes, many of which become macrophages when they migrate into tissues Tissue-resident macrophages, which are initially derived from yolk sac or hematopoietic precursors during fetal life 18  FUNCTIONS F MACROPHAGE A major function of monocyte-derived macrophages in host defense is to ingest microbes by the process of phagocytosis and then to kill the ingested microbes The mechanisms of phagocytosis and killing of microbes include 1. The formation of cytoplasmic membrane–bound organelles that contain the microbes 2. The fusion of these organelles with lysosomes 3. The enzymatic generation of reactive oxygen and nitrogen species in the lysosome that are toxic to microbes 4. The digestion of microbial proteins by proteolytic enzymes 19  FUNCTIONS F MACROPHAGE Tissue-resident macrophages function as sentinel cells that sense the presence of microbes and respond by secreting cytokines that initiate and then amplify the protective response against the microbes Macrophages ingest necrotic host cells, including cells that die in tissues because of the effects of toxins, trauma or interrupted blood supply, and neutrophils that die after accumulating at sites of infection 20 FUNCTIONS F MACROPHAGE Macrophages serve as antigen-presenting cells (APCs) that display fragments of protein antigens to T lymphocytes Macrophages promote the repair of damaged tissues by stimulating new blood vessel growth (angiogenesis) and synthesis of collagen-rich extracellular matrix (fibrosis) 21  SUBSETS OF MACROPHAGES Macrophages can acquire distinct functional capabilities, depending on the types of activating stimuli to which they are exposed (cytokines) Some of these cytokines activate macrophages to become efficient at killing microbes, called classical activation, and these cells are called M1 macrophages Other cytokines activate macrophages to promote tissue remodeling and repair, called alternative activation, and these cells are called M2 macrophages 22  DIFFERENCE BETWEEN MACROPHAGES AND NEUTROPHILS 23  MAST CELLS, BASOPHILS, AND EOSINOPHILS Mast cells, basophils, and eosinophils are three additional cell types that play roles in innate and adaptive immune responses All three share the common property of having cytoplasmic granules filled with various inflammatory and antimicrobial mediators, which are released from the cells upon activation Another common feature of these cells is their involvement in immune responses that protect against helminths and reactions that cause allergic diseases 24  MAST CELLS They are bone marrow–derived cells that are most abundant in the skin and mucosal epithelia Their cytoplasm contains numerous membrane-bound granules, which are filled with preformed inflammatory mediators, such as histamine Upon activation, they release many potent inflammatory mediators that defend against infections by helminthic parasites or cause symptoms of allergic diseases Various stimuli can activate mast cells to release the cytoplasmic granule contents into the extracellular space, as well as to synthesize and release cytokines and inflammatory lipid mediators 25  MAST CELLS The released histamine and other mediators promote changes in the blood vessels that cause inflammation Mast cells express high-affinity plasma membrane receptors for a type of antibody called IgE and are usually coated with these antibodies. When the antibodies on the mast cell surface bind antigen, signaling events are induced that lead to mast cell activation Mast cells are also activated when they recognize microbial products, independent of IgE, and in this way they function as tissue sentinels of the innate immune system. 26  BASOPHILS Basophils are blood granulocytes with many structural and functional similarities to mast cells Like other granulocytes, basophils are derived from hematopoietic precursors, mature in the bone marrow (from progenitors distinct from those of mast cells), and circulate in the blood Although they are normally not present in tissues, basophils may be recruited to some inflammatory sites 27  EOSINOPHILS Eosinophils are bone marrow–derived and circulate in the blood, from where they may be recruited into tissues Eosinophils are granulocytes that express cytoplasmic granules containing enzymes that are harmful to the cell walls of parasites but also can damage host tissues Various membrane receptors on eosinophils, such as Fc receptors for IgA and IgG, can generate signals that activate the cells to release their granule contents 28  NATURAL KILLER CELLS(NK) NK cells are cytotoxic cells that play important roles in innate immune responses, mainly against viruses and intracellular bacteria to produce IFN-γ, which activates macrophages to destroy phagocytosed microbes NK cells, like CTLs, have granules that contain proteins that mediate killing of target cells. When NK cells are activated, granule exocytosis releases these proteins adjacent to the target cells 29  NATURAL KILLER CELLS One NK cell granule protein, called perforin, facilitates the entry of other granule proteins, called granzymes, into the cytosol of target cells. The granzymes are proteolytic enzymes that initiate a sequence of signaling events that cause death of the target cells by apoptosis NK cell recognition of infected cells is regulated by a combination of activating and inhibitory receptors. Inhibitory receptors recognize class I major histocompatibility complex (MHC) molecules, because of which NK cells do not kill normal host cells but do kill cells in which class I MHC expression is reduced, such as virus infected cells 30  Innate Lymphoid Cells(ILCS) ILCs are cells with lymphocyte morphology and functions similar to those of T lymphocytes, but they do not express clonally distributed T cell antigen receptors ILCs are rare in the blood and are present mostly in tissues, especially mucosal tissues such as the lung and intestines 31  DENDRITIC CELLS (DCS) DCs are tissue-resident and circulating cells that detect the presence of microbes and initiate innate immune defense reactions They capture microbial proteins for display to T cells to initiate adaptive immune responses 32  DENDRITIC CELLS (DCS) Subsets and functions of Dendritic Cell classical DCs that can be further divided into two main subsets called major, or cDC2, and cross-presenting, or cDC1 cDC2 is the most numerous subset and is potent at capturing exogenous antigens and inducing CD4 + T cell responses The cDC1 subset is specialized to present antigens to naive CD8 + T cells by a process called cross presentation, this subset can also present antigens to CD4 + cells. 33  DENDRITIC CELLS (DCS) Plasmacytoid DCs produce the antiviral cytokine type I interferon (IFN) in response to viruses and may capture blood borne microbes and carry their antigens to the spleen for presentation to T cells Monocyte-derived DCs include cells with functions similar to those of cDCs but are derived from monocytes that were recruited into tissue inflammatory sites Langerhans cells are DCs found in the epidermis that share functions with cDCs but are developmentally related to tissue-resident macrophages 34  LYMPHOCYTES Lymphocytes, the unique cells of adaptive immunity Each clone of T and B lymphocytes expresses antigen receptors with a single specificity, which is different from the specificities of the receptors in all other clones There are subsets of B and T lymphocytes with distinct phenotypic and functional characteristics 35  DEVELOPMENT OF LYMPHOCYTES Lymphocytes, like all blood cells, arise after birth from stem cells in the bone marrow All lymphocytes go through complex maturation stages during which they express antigen receptors and acquire the functional and phenotypic characteristics of mature cells The development of lymphocytes occurs in the primary lymphoid organs These include the bone marrow, where precursors of all lymphocytes arise and B cells mature, and the thymus, where T cells mature 36  DEVELOPMENT OF LYMPHOCYTES Naive B and T cells are mature lymphocytes that have not been previously stimulated by antigen When they encounter antigen, they proliferate and differentiate into effector lymphocytes that have functions in protective immune responses Effector B lymphocytes are antibody secreting plasma cells. Effector T cells include cytokine secreting CD4 + helper T cells and CD8 + CTLs Some of the progeny of antigen-activated B and T lymphocytes differentiate into memory cells that survive for long periods in a quiescent state. These memory cells are responsible for the rapid and enhanced responses to subsequent exposures to 37 antigen.  DEVELOPMENT OF LYMPHOCYTES Maturation of lymphocytes 38  DEVELOPMENT OF LYMPHOCYTES Populations of Lymphocytes Distinguished by History of Antigen Exposure 39 JUST TRY NOT TO LAUGH What the Memory T cell to the microbe 40  SUBSETS OF B LYMPHOCYTES Follicular B cells, the most numerous type of B cells in the body, are found in lymphoid tissues and blood. They give rise to most of the high-affinity antibodies and memory B cells B-1 and marginal zone B cells make up a minority of B cells and produce antibodies with limited diversity. B-1 cells are found mainly in mucosal tissues and the peritoneal and pleural cavities, whereas marginal zone B cells are present only in the spleen in rodents but can be found in the circulation of humans 41  SUBSETS OF T LYMPHOCYTES The two major T cell subsets are defined by the cell surface expression of the CD4 and CD8 proteins T cells are the mediators of cellular immunity: CD4 + T cells are helper T lymphocytes or their naive precursors, and CD8 + T cells are CTLs or their precursors Both CD4 + and CD8 + T cells express antigen receptors called αβ T cell receptors (TCRs) CD4 + helper T cells secrete cytokines that act on various other cells, including other T lymphocytes, B cells, and macrophages 42  SUBSETS OF T LYMPHOCYTES The differentiation of naive CD4 + T cells into subsets of helper T cells is induced by: 1. Cytokines produced by antigen presenting cells 2. The T cells themselves 3. By other cells It is also clear that some of the effector T cells may convert from one cytokine profile to another in response to changes in activation conditions. The extent and significance of plasticity or stability of differentiated effector T cells remain topics of active research 43  CYTOTOXIC T LYMPHOCYTES T cells of the CD8 + subset proliferate and differentiate into cytotoxic T lymphocytes (CTLs), which express cytotoxic granules and can kill infected cells The differentiation of CD8 + T cells into functional CTLs and memory cells requires recognition of antigen presented by dendritic cells, signals from CD4 + helper T cells in some situations, costimulation, and cytokines 44  MECHANISMS OF CYTOTOXIC T LYMPHOCYTE – MEDIATED KILLING OF TARGET CELLS Cytotoxic T lymphocytes (CTLs) kill target cells by two main mechanisms: Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. The granzymes are delivered into the cytoplasm of the target cells by a perforin-dependent mechanism, and they induce apoptosis FasL is expressed on activated CTLs, engages Fas on the surface of target cells, and induces apoptosis 45  ROLES OF CD8 + CYTOTOXIC T LYMPHOCYTES IN HOST DEFENSE In infections by intracellular microbes, the killing activity of CTLs is important for eradication of the reservoir of infection Destruction of infected cells by CTLs is a cause of tissue injury in some infectious diseases (for instance, in infection by hepatitis B and C viruses, the infected liver cells are killed by the host CTL (and NK cell) response and not by the viruses) 46  T HELPER CELLS Naive CD4 + T lymphocytes may differentiate into different types of specialized effector T cells, including: Th1 cells that secrete interferon-γ (IFN-γ), which mediate defense against intracellular microbes Th2 cells that secrete interleukin-4 (IL-4) and IL-5, which favor IgE- and eosinophil/mast cell– mediated immune reactions against helminths Th17 cells, which promote inflammation and mediate defense against extracellular fungi and bacteria CD4 + regulatory T cells (Treg)are a third subset of T cells expressing αβ receptors; their function is to inhibit immune responses 47  T HELPER CELLS Role of T cells in eradicating infections CD4 + T cells recognize antigens of phagocytosed and extracellular microbes and produce cytokines and cell surface molecules that recruit and activate the phagocytes to kill the microbes 48 THANKS FOR YOUR ATTENTION! 49