Lymphoid Tissues & Transition Sp24 Notes PDF

3/14/24 The Immune System Dr. Dalia Zakaria 1 Adaptive Immunity IV Components of the Adaptive Immune System Secondary Lymphatic Organs and Tissues Textbook Reading: Chapter 1 (pp. 15 – 21) 2 1 3/14/24 What Do You Need to Learn? Components of the immune system (an overview) Components of the innate i...

3/14/24 The Immune System Dr. Dalia Zakaria 1 Adaptive Immunity IV Components of the Adaptive Immune System Secondary Lymphatic Organs and Tissues Textbook Reading: Chapter 1 (pp. 15 – 21) 2 1 3/14/24 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 By the end of this module, you should understand the following: The Peripheral lymphoid tissues, their structure and functions How do the lymphocytes enter and leave the lymph nodes? How do the antigens and APCs enter the lymph nodes? How the different types of cells are attracted to the right compartment of the lymph nodes The structure and function of the spleen The structure and function of the cutaneous and mucosal tissues 4 2 3/14/24 Initiation of the Adaptive Immune Response Why do antigens and lymphocytes travel to the lymph nodes? 5 How do rare specific lymphocytes find their specific antigens? Very few naive lymphocytes are specific for any one antigen, as few as 1 in 105 or 106 circulating lymphocytes This small fraction of the body’s lymphocytes needs to locate and react rapidly to the antigen Because of the vast surface area of the epithelial barriers and the large volume of blood, connective tissues, and internal organs, it would be impossible for lymphocytes of all possible specificities to efficiently patrol all these sites searching for foreign invaders Instead, antigens are taken to the lymphoid organs through which lymphocytes recirculate 6 3 3/14/24 Peripheral Lymphoid Organs and Tissues The anatomic organization of peripheral lymphoid organs enables APCs to concentrate antigens in these organs and lymphocytes to locate and respond to the antigens An important function of the lymphoid organs is to bring these rare cells together after stimulation by antigen so they interact The major peripheral lymphoid organs share many characteristics but also have some unique features 7 Peripheral Lymphoid Organs and Tissues Lymph nodes Spleen Lymphoid tissues 8 4 3/14/24 Lymph Nodes Lymph nodes are encapsulated nodular aggregates of lymphoid tissues located along lymphatic channels throughout the body Lymph constantly leaks out of blood vessels in all epithelia and connective tissues and is drained by lymphatic vessels to the lymph nodes and back into the blood circulation The lymph contains a mixture of substances absorbed from epithelia and tissues DCs pick up antigens of microbes from epithelia and other tissues and transport these antigens to the lymph nodes The net result of these processes of antigen capture and transport is that the antigens of microbes entering through epithelia or colonizing tissues become concentrated in draining lymph nodes 9 Lymph Nodes It is important to know the following: How do lymphocytes enter the lymph nodes? Naïve B and T cells leave blood circulation and enter the lymph nodes through high endothelial venules (HEV) T cells go to the T cell zone B cells go to the B cell zone (follicle) How do antigens and APCs enter the lymph nodes? Antigens and APCs enter the lymph nodes through the afferent lymphatic vessels Naïve cells that have not encountered specific antigens leave the lymph nodes through the efferent lymphatic vessels and pass through other lymph nodes, then into larger and larger vessels until they enter the main lymphatic vessel (the thoracic duct) which carries them back into blood 10 5 3/14/24 High Endothelial Venules (HEV) High Endothelial Venule HEV 11 Lymph Nodes 12 6 3/14/24 Lymph Nodes B cells and T cells migrate to follicles and T cell zone respectively in response to chemokines 13 Spleen The spleen is a highly vascularized abdominal organ that serves the same role as that of lymph nodes in responses to blood-borne antigens Blood entering the spleen flows through a network of channels (sinusoids) Blood-borne antigens are captured and concentrated by dendritic cells and macrophages in the spleen The spleen contains abundant phagocytes, which ingest and destroy microbes in the blood T lymphocytes are concentrated in periarteriolar lymphoid sheaths surrounding small arterioles, and B cells reside in the follicles 14 7 3/14/24 Spleen White pulp 15 Cutaneous and Mucosal Immune System Ø Specialized collections of lymphoid tissues and APCs located in and under the epithelia of the skin and the gastrointestinal and respiratory tracts respectively This includes Mucosa associated lymphoid tissue (MALT) Gut associated lymphoid tissue (GALT) Bronchus associated lymphoid tissue (BALT) 16 8 3/14/24 Cutaneous and Mucosal Immune System Most of the immune cells in these tissues are scattered beneath the epithelial barriers but some lymphocytes and APCs are organized in a similar way as in lymph nodes (tonsils and Peyer’s patches) Cutaneous and mucosal lymphoid tissues are sites of immune responses to antigens that breach epithelia At any time, at least 25% of the body’s lymphocytes are in the mucosal tissues and skin and many of these are memory cells They are able to respond to pathogens but not to the enormous numbers of harmless commensal microbes present at the epithelial barriers which is accomplished by several mechanisms that suppress the T lymphocytes 17 Mucosal Immune System Intraepithelial lymphocytes (ILE), most of them are a special type of lymphocytes that have limited diversity 18 9 3/14/24 Mucosal Immune System Lymphatic drainage to the nearest lymph node 19 Mucosal Immune System M cells promote the transport of antigens from lumen to underlying tissues Cells in the lamina propria provide innate and adaptive immune response 20 10 3/14/24 Mucosal Immune System M cells promote the transport of antigens from lumen to underlying tissues Cells in the lamina propria provide innate and adaptive immune response 21 The Immune System 22 11 3/14/24 Adaptive Immunity V Transition from Innate to Adaptive Immunity Textbook Reading: Chapter 3 23 What Do You Need to Learn? Components of the immune system (an overview) Components of the innate immune system Mechanisms of innate immune responses 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) Transition from innate to adaptive immune response Mechanisms of lymphocytes activation Effector mechanisms of the adaptive immune responses 24 12 3/14/24 Objectives By the end of this module, you should understand the following: The transition from innate to adaptive immunity The steps of antigen presentation and the role of MHC in this process The difference between class I and class II MHC pathways What is cross presentation? 25 Transition from Innate to Adaptive Immunity Antigen presentation is essential for activation of lymphocytes Antigen presentation is performed by Antigen Presenting Cells (APCs) such as dendritic cells Tissue resident APCs capture and process microbes to generate peptides that are displayed on the cell surface bound to MHC molecules Both DCs and macrophages are professional APCs 26 13 3/14/24 Steps of Antigen Presentation and Lymphocytes Activation Protein antigens of microbes that enter the body are captured mainly by dendritic cells and concentrated in the peripheral lymphoid organs, where immune responses are initiated 1. 2. 3. 4. 5. 6. 7. Capture of antigens Activation of the dendritic cells and antigen processing Migration of the antigen-carrying cells to lymph nodes Entry of lymphocytes to the lymph nodes Antigen presentation to T cells by APCs cells Activation, proliferation and differentiation of T cells Activation, proliferation and differentiation of B cells 27 Capture of Antigens, Activation and Migration of DCs Classical DCs use various membrane receptors to bind microbes They are also activated by the inflammatory cytokines such as TNF-α and IL-1 produced by the other innate immune cells When activated, classical DCs lose their adhesiveness for epithelia and express CCR7 specific for chemokines produced by lymphatic endothelium and stromal cells in the T cell zones of lymph nodes Chemokines direct DCs to migrate through lymphatic vessels to the lymph nodes draining that epithelium Activation of DCs also induces processing the internalized antigens (discussed next) 1 2 3 28 14 3/14/24 Antigen Processing by DCs Extracellular proteins that are internalized by specialized DCs are processed in by antigen presenting cells and displayed on MHC molecules 29 MHC I and MHC II 30 15 3/14/24 Peptide Binding to MHC Molecules There are pockets in the floors of the peptide-binding clefts of most MHC molecules. Some of the amino acids in the peptide antigens fit into these MHC pockets and anchor the peptides in the cleft of the MHC molecule; these amino acids are called anchor residues Other residues of the bound peptide project upward and are recognized by the antigen receptors of T cells 31 Peptide Binding to MHC Molecules 32 16 3/14/24 Peptide Binding to MHC Molecules Each individual has only a few different MHC molecules that must be able to present a vast number and variety of protein antigens Each MHC molecule can present different peptides (broad specificity for peptide binding), but only one peptide at a time There are about 105 MHC molecules on the surface of an APC. 0.1% - 1% of them are enough to display a peptide for a T cell and they stay bound for up to days for some peptides MHC molecules can display self peptides derived from the individual’s own proteins, as well as peptides from foreign (i.e., microbial) proteins. Why do not T cells attack the self antigens? 33 MHC I All nucleated cells can present class I MHC–associated peptides to CD8+ T cells Class I MHC molecules acquire peptides from cytosolic proteins Protein antigens of microbes that live in the cytoplasm of infected cells enter the class I MHC pathway of antigen processing As a result, these proteins are recognized by CD8+ cytotoxic T lymphocytes, whose function is to kill infected cells 34 17 3/14/24 MHC II All APCs as well other cell types, such as vascular endothelial cells, express MHC II In the thymus, epithelial cells express MHC II and play a role in the maturation and selection of T cells Protein antigens of microbes that are endocytosed from the extracellular environment by macrophages and B lymphocytes enter the class II MHC pathway of antigen processing These proteins are recognized by CD4+ helper T lymphocytes, which activate macrophages to destroy phagocytosed microbes and activate B cells to produce antibodies against extracellular microbes and toxins 35 Antigen Processing by DCs Extracellular proteins that are internalized by specialized DCs are processed in late endosomes and lysosomes and displayed by class II MHC molecules Proteins in the cytosol of any nucleated cell are processed in proteolytic structures called proteasomes and displayed by class I MHC molecules They are designed to sample all the proteins present in the extracellular and intracellular environments 36 18 3/14/24 Class II MHC Pathway MHCI MHCII 37 Class II MHC Pathway MHCI MHCII Pathogens are ingested by APCs and processed in the endosome 38 19 3/14/24 Class II MHC Pathway MHCI MHCII Pathogens are ingested by APCs and processed in the endosome 39 Class II MHC Pathway MHCI MHCII Pathogens are ingested by APCs, processed in the endosome and displayed on MHCII The antigen is now ready to be presented to CD4+ cells 40 20 3/14/24 Class I MHC Pathway MHCI MHCII Antigen presentation on MHCI requires the antigen to be in the cytosol If the pathogen can infect the DC, it will enter the cytosol and it will be delivered to MHCI on the cell surface If the pathogen can not infect the DC, certain DCs can ingest infected host cells, dead tumor cells, microbes, etc. and transport them from the phagosome into the cytosol, where they are displayed on MHC I 41 Cross Presentation MHCI MHCII Cross presentation is the presentation of the antigen on both MHCI and MHCII to CD4+ and CD8+ cells respectively by the same APC 42 21 3/14/24 Cross Presentation Intracellular pathogens which can infect the APC will reach the cytosol Some viruses may infect only particular cell types and not dendritic cells, and these infected cells may not be APCs A subset of classical DCs can ingest infected host cells, dead tumor cells, microbes, etc., and transport them into the cytosol, where they are processed and displayed on MHC I By convention, the term cross-presentation is applied to CD8+ T cells (cytotoxic T lymphocytes) recognizing class I MHC–associated antigens The same cross-presenting APC may display class II MHC–associated antigens from the microbe for recognition by CD4+ helper T cells 43 Cross Presentation Some DCs can transport ingested antigens from the endosome into the cytosol, process them and present them on MHC I molecules Consequently, they will be able to present the antigens to both CD4+ and CD8+ on MHCII and MHCI respectively which is called cross presentation 44 22 3/14/24 Steps of Antigen Presentation and Lymphocytes Activation 1. Capture of antigens 1. Activation of the dendritic cells 2. Migration of the antigen-carrying cells to lymph nodes 3. Entry of lymphocytes to the lymph nodes 4. Antigen presentation to T cells by APCs cells 5. Activation, proliferation and differentiation of T cells 6. Activation, proliferation and differentiation of B cells 45 Entry of Lymphocytes to the Lymph Nodes Circulating naïve lymphocytes enter the lymph nodes from blood through specific adhesion molecules which are expressed on both endothelial cells and lymphocytes B and T cells express 2 different chemokines receptors which are produced in the B cell zone and the T cell zone respectively 46 23 3/14/24 How will B and T cells go to different zones of the lymph nodes? 47 24