BIOC39 W2024 - Lecture 2 Cells and Tissues PDF

Cells, Tissues and Organs of the Immune System Lecture 2 Prof. Trisha Mahtani Instructor, BIOC39 Friday, January 19th, 2024 1 This week: Lecture 2 Date Jan 19th Lecture 2 Topic Cells and Tissues of Immune System Readings Chp 1 Due dates N/A 2 Office Hours Mondays 2-3pm and Wednesdays 1-2pm...

Cells, Tissues and Organs of the Immune System Lecture 2 Prof. Trisha Mahtani Instructor, BIOC39 Friday, January 19th, 2024 1 This week: Lecture 2 Date Jan 19th Lecture 2 Topic Cells and Tissues of Immune System Readings Chp 1 Due dates N/A 2 Office Hours Mondays 2-3pm and Wednesdays 1-2pm (in-person). Open to discussing course content, immunology, careers, etc. Office: SY210A Email me for an appointment slot(s) either in person or on zoom if neither of these work! Will add additional office hours for exams. 3 uoft.me/utscnotes [email protected] 5 Re-visit: What is Vaccination? A. B. C. D. A procedure that induces an immune response. A procedure that provides short-term protection against pathogens. A procedure that desensitizes an individual to environmental pathogens. A procedure that involves administration of pathogenic forms of diseasecausing agents. Our immunity to the flu only lasts for one season and vaccination also only lasts one season due to rapid changes in virus strains (mutations). Still is “long term” when facing what you are immunized against. Universal vaccine in works to protect us longer term! 6 True or False? The Adaptive immune system is fast-acting while the Innate immune system is pathogen-specific. A. True B. False 7 Reminder: Self vs. Non-self = Tolerance Self = commensal bacteria and our own tissues/cells. Non-self = invading pathogens 10 REMINDER: Phases of the Immune Response Type of Immune Response Typical time after infection to start of response Duration of response Minutes Days Activation of cells Hours Days Expansion of cells Days Weeks Days - Weeks Can be lifelong Innate Immunity Adaptive Immunity Immunological Memory 11 The Cells of the Immune System 12 Stem Cells (1) the ability to regenerate or “self-renew” (2) the ability to differentiate from young, immature cells into diverse and mature cell types with specialized function. Embryonic stem cells = Pluripotent = give rise to all cell types in the body Adult stem cells = Multipotent = give rise to tissue-specific cell types 13 Hematopoiesis occurs in primary lymphoid organs All our immune cells originate from a stem cell = Hematopoietic stem cell (HSC). Hematopoiesis = maturation of HSC into immune cells. Adult HSCs = multipotent. 14 Hematopoiesis occurs in primary lymphoid organs Immune cell development occurs in stem cell niches where HSCs reside. These niches change throughout embryonic development. Primary site in adulthood = bone marrow. 15 Primary Lymphoid Tissue: Bone Marrow Adult immune cells develop in primary lymphoid organs (bone marrow and thymus). HSCs → Immature Precursors → Specialized, mature immune cells. Stromal cells = specialized cells maintain the niche for immune cell development 16 Primary Lymphoid Tissue: Thymus One specific immune cell precursor leaves the bone marrow and develops to a mature immune cell in the thymus. Discovered as a site of immune cell development after being thought to be a useless organ! 17 White Blood Cells Make Up Our Immune Cells HSCs give rise to red blood cells (erythrocytes) and white blood cells (leukocytes). Leukocytes arise from two progenitor cells: • Myeloid progenitor = myeloid cells • Lymphoid progenitor = lymphocytes 18 Myeloid Cells are Important for Innate Immunity Myeloid progenitors give rise to: • Leukocytes in the innate immune system • Red Blood Cells (RBCs) • Megakaryocytes and Platelets for clotting Peripheral Tissues Myeloid Leukocytes = Monocytes, Granulocytes, Mast Cells, and Dendritic Cells Monocytes: Macrophages (and dendritic cells) Granulocytes (Polymorphonuclear Cells): Eosinophils, Basophils, Neutrophils (and Mast cells) 19 Bone Marrow Myeloid Cells: Granulocytes Granulocytes (Polymorphonuclear Cells): Eosinophils, Basophils, Neutrophils, Mast Cells Peripheral Tissues • First responders to infection • Multi-lobed nuclei • Cytoplasmic granules • Intracellular membrane-bound vesicles • Release contents during infection = Degranulation Bone Marrow 20 Myeloid Cells: Granulocytes Granules are different for each cell type (staining is different) • Contain proteins to harm pathogens, recruit immune cells or remodel tissue 21 Myeloid Cells (Granulocytes): Neutrophils • • • • Most abundant leukocyte (50-70%) Very short-lived Highly mobile Infection -> Leukocytosis = temporary increase in neutrophil development • Neutrophils are phagocytes • Granules have anti-microbial properties and help remodel tissue • Main component of pus! 22 Myeloid Cells (Granulocytes): Neutrophils 23 Neutrophil Extracellular Traps (NETs) Kill Pathogens Neutrophils undergo cell death (NETosis) releasing extracellular traps containing DNA and proteins. Fuchs, Tobias A., et al. The Journal of cell biology 176.2 (2007) 24 Papayannopoulos, V. Nature Reviews Immunology (2018). Myeloid Cells (Granulocytes): Eosinophils • 1-3% of leukocytes • Mobile • Important for parasite infections • Granules damage parasite membranes • Secrete cytokines regulating immune responses Contribute to allergies and asthma where parasites are not common (hygiene hypothesis). 25 Myeloid Cells (Granulocytes): Basophils • <1% of leukocytes • Non phagocytic • Important for parasite infections • Granules contain histamine • Increases immune cell recruitment/tissue remodeling • Secrete cytokines regulating immune responses Contribute to allergies and asthma where parasites are not common (hygiene hypothesis). 26 Myeloid Cells (Granulocytes): Mast Cells • <1% of leukocytes • Non phagocytic • Similar to Basophils • Important for parasite infections • Granules contain histamine • Increases immune cell recruitment/tissue remodeling Contribute to allergies and asthma where parasites are not common (hygiene hypothesis) 27 Myeloid Cells: Monocytes Peripheral Tissues Monocytes • 2-12% of leukocytes • Migrate and differentiate into tissueresident phagocytes Bone Marrow • Inflammatory monocytes = enter tissues upon infection • Patrolling monocytes = crawl along and monitor blood vessel repair 29 Myeloid Cells: Macrophages Inflammatory Monocytes differentiate into Macrophages Macrophages = expert phagocytes & professional antigen presenting cells (pAPCs) 30 Tissue-Resident Macrophages Tissue-Resident macrophages clear infection and perform tissue specific functions Tissue Resident Macrophage name Tissue-specific function (in addition to pAPC) Brain Microglia Synaptic pruning (Neural circuit development) Lung Alveolar Macrophage Remove pollutants, microbes, surfactants Liver Kupffer cell Scavenge RBCs Kidney Resident Kidney Macrophage Regulate inflammation to blood antigens Skin Langerhans cell Skin Immunity/Tolerance Spleen Red Pulp Macrophage Scavenge RBCs, recycle iron Intestine Lamina Propria Macrophage, Intestinal Muscularis Macrophage Gut immunity/tolerance Regulate peristalsis Bone Marrow Bone Marrow Macrophage Maintain niche for blood cell development, clear neutrophils Lymph Node Subcapsular Sinus Macrophage Trap antigen Heart Cardiac Macrophage Clear dying heart cells 31 How Tattoos Work: Macrophages Dermal macrophages are what make permanent tattoos possible! Also why tattoo removal is so difficult! Baranska et al. (2018). J ex med. 32 Dendritic Cells Bridge Innate and Adaptive Immunity Peripheral Tissues Bone Marrow Dendritic cell (DC) origins are still not well known, many different types Arise from both innate and adaptive. 33 Proteins Help Mediate Cell-Cell Interactions Some lymphocytes have antigen receptors (B cells and T cells). B cell receptors (BCR) can recognize antigen in any form, particulate or soluble e.g. protein, lipid, carbohydrate, etc. T cell receptors (TCR) can only recognize antigen as a peptide presented on an MHC molecule. Require Antigen Presentation!! 34 Antigen Presentation Antigen Presentation = displaying peptides of antigen/pathogen Peptides are presented on Major Histocompatibility Complex (MHC) Molecules • All cells have surface MHC I (to indicate infection, cancer, abnormality) • Professional antigen presenting cells (pAPCs) have surface MHC II pAPCs get activated, phagocytose pathogens, digest proteins into peptides, load them onto MHC II 35 Professional Antigen Presenting Cells (pAPCs) 36 Proteins Help Mediate Cell-Cell Interactions Immune cells express many Cluster of Differentiation (CD) molecules to help them perform functions and interact with cells/pathogens. We can tell cells apart by their CD molecule combos (CD+ and CD-) because every 37 immune cell has a different one. Proteins Help Mediate Cell-Cell Interactions Cell – cell interactions = Immunological Synapse = Mix of receptors including CD molecules, integrins (adhesion molecules), MHC molcules and antigen receptors 38 Immunology Toolbox: Flow Cytometry A heterogeneous population of cells can be distinguished by size and shape. Fluorescent antibodies recognizing specific proteins can further differentiate the cells in the sample. These are distinguished by a laser that measures size (forward scatter), shape/complexity (side scatter) and fluorescence (emitted colour). 39 40 Flow Cytometry Example If you collected cells from a spleen and added antibodies for CD19 (protein on B cells) and antibodies for CD3 (protein on T cells). This is the resulting flow cytometry plot from the sample, what do the plots and the quadrants on the 2-D plot mean? Q1 Q2 C D 19 Q3 CD3 CD3 Q4 41 Myeloid and Lymphoid Cells: Dendritic Cells Dendritic cell (DC) have dendrites = long membrane extensions that capture antigen as pAPCs 44 Myeloid and Lymphoid Cells: Dendritic Cells Immature DCs capture antigen through phagocytosis, endocytosis or pinocytosis (intake of extracellular fluid) and get activated. 45 Lymphoid Cells are Important for Adaptive Immunity Lymphoid progenitors give rise to: • Lymphocytes in the adaptive immune system • Innate Lymphoid Cells (ILCs) Peripheral Tissues Lymphocytes = ILCs, B cells, T cells (and dendritic cells • ILCs are part of innate immunity • T cells differentiate into Helper or Cytotoxic (Killer) T cells • B cells differentiate into Plasma Cells to secrete antibodies Bone Marrow 46 B Lymphocytes Discovered in the Bursa of Fabricus in chickens • Every B cell (B lymphocyte) has a unique B cell receptor (BCR) • BCR is membrane-bound, surface version of an antibody • Up to 3 x 105 BCRs on a single B cell 47 B Lymphocytes • Naïve, mature B cells are activated by antigen • BCRs recognize antigen in any form (soluble and particulate) triggering activation of the B cell • Activated B cells are pAPCs • Presenting antigen to T cells gives 2nd activation signal 48 Plasma Cells Some activated B cells differentiate into Plasma cells • Plasma cells have no surface, membrane-bound BCR • Secrete 100s-1000s of antibody per second • Some are short-lived and some are long-lived 49 T Lymphocytes T cells (T lymphocytes) develop in the Thymus • T cells have a T Cell Receptor (TCR) • TCRs recognize peptides attached to MHC molecules of APCs (MHC I) and pAPCs (MHC II) • T cells are either helpers or cytotoxic • Distinguished by a specific molecule: Helper T cell = CD4, Cytotoxic T cell = CD8 50 Helper T Lymphocytes • Helper T cells (CD4) recognize pAPCs • Cytotoxic T cells (CD8) recognize all the cells in our body • Helper T cells: Cytotoxic T cells = 2:1 in our blood • Helper T cells get activated by pAPCs and also activate the pAPCs (e.g. B cells) • Helper T cell subtypes are specific to the type of pathogen (based on cytokines) 51 Helper T Lymphocytes • Helper T cell subtypes are specific to the type of pathogen • The environment in which they get activated influences this • Named for the cytokines they secrete • Regulatory T cells (Treg) are inhibitory to control inflammation 52 Cytotoxic T Lymphocytes Cytotoxic T cells (TC) monitor our cells for infection • Eliminate cells presenting non-self antigens e.g. cancer cells, virus infected cells • Differentiate into Cytotoxic T lymphocyte (CTL) upon recognition of non-self antigen on cells • CTLs release cytotoxins that poke holes in cell membrane and cause apoptosis 53 pAPCs Present Both MHC Molecules 54 55 Innate Lymphoid Cells (ILCs) Innate Lymphoid Cells (ILCs) • Newly discovered cell type, under investigation • No antigen-specific receptors (unlike B cells and T cells) • 3 groups: ILC1, ILC2, ILC3 • Based on cytokines like Helper T cells 56 Innate Lymphoid Cells (ILCs) • Natural Killer (NK) cells are wellknown ILC • 5-10% of lymphocytes • Cytotoxic cells that attack abnormal cells • Recognize a lack of MHC molecules and release cytotoxic granules to kill the cell 57 Percentages of Immune Cell Populations Cell type Cells/mm3 Total Leukocytes (%) Lifespan Red blood cell (RBC) 5 x 106 - 120 days Platelet 2.5 x 105 - 5-10 days Neutrophil 3.7 - 5.1 x 103 50 - 70 6 hours - 2 days Monocyte 1 – 4.4 x 102 2 - 12 Days - months Eosinophil 1 – 2.2 x 102 1-3 5 - 12 days Basophil <1.3 x 102 <1 Hours - days Mast Cell <1.3 x 102 <1 Hours - days 1.5 – 3.0 x 103 20 - 40 Days - years T cells 0.54 – 1.79 x 103 7 - 24 B cells 0.07 – 0.53 x 103 1 - 10 Total Leukocytes 7.3 x 103 Myeloid Cells Lymphocytes 58 Tissues and Organs of the Immune System 59 Developing Immune Cells Travel Through the Body 60 Lymphatic System Lymphatic system = network of vessels with lymph (fluid derived from blood plasma) Lymph vessels also return fluid that leaked from capillaries to the bloodstream, preventing lymphedema. Thoracic duct = largest lymph vessel, drains into bloodstream 61 Lymphatic System Immune cells are recruited from blood vessels to the site of infection (vascular permeability) and then “drain” or travel, along with antigen, to secondary lymphoid organs. Most naïve lymphocytes reside in secondary lymphoid organs. 62 Cytokines and Chemokines There are over 60 cytokines • Recruit nearby immune cells with the specific cytokine receptor • Enhance the immune cell function There are over 50 chemokines • Recruit cells with specific chemokine receptor out of the bloodstream and into infected tissue • Also organize the various cells in lymphoid tissues into discrete regions where specialized responses can take place. 63 Secondary Lymphoid Tissue: Lymph Nodes Lymph nodes are highly specialized in regulating immune responses. Typically the first lymphoid organ to encounter antigen. 64 Secondary Lymphoid Tissue: Lymph Nodes Cortex = Outermost tissue layer Paracortex = Middle tissue layer Medulla = Innermost tissue layer Antigen and immune cells enter the lymph node through incoming (afferent) lymphatic vessel in the cortex. Exit from the outgoing (efferent) lymphatic vessel in the medulla. Immune cells enter from the blood by the high endothelial venule (HEV). 65 Secondary Lymphoid Tissue: Lymph Nodes Cortex = B cells (Follicle) Paracortex = T cells (T cell zone) Paracortex and Cortex = Macrophages and DCs (resident and migrating) Medulla = Plasma cells 66 Secondary Lymphoid Tissue: Lymph Nodes Fibroblastic Reticular Cells (FRCs) make up network of fibers that APCs position themselves on. This fibroblastic reticular cell conduit (FRCC) system guides T-cells. Follicular dendritic cells (FDCs) are not actually DCs! FDC network guides B cells. 67 Germinal Centers Naïve B cell follicles = primary follicles. B cell follicles with activated B cells (germinal center) = secondary follicles. Germinal centers are where B cells proliferate in response to antigen, creating B cells with even better BCRs (and resulting antibodies) towards the antigen. 68 Secondary Lymphoid Tissue: Spleen The spleen coordinates immune responses towards bloodborne pathogens. The spleen has no lymphatic vessels. Red pulp surrounds white pulp separated by the marginal zone. 69 Secondary Lymphoid Tissue: Spleen Sergey Charapov, a trapeze artist, arrived at the hospital by ambulance following a serious stage accident at a Las Vegas show. There was severe damage to his spleen, and bleeding in the abdominal cavity was documented. An emergency splenectomy was performed to prevent further hemorrhaging, a potentially lifethreatening complication of splenic rupture. Which of the following recommendations is Sergey likely to receive from his attending physician? A. B. C. D. E. Transplantation of a healthy spleen Bone marrow transplant to replace lost immune cells Immunization against bloodborne pathogens and antibiotics for life Antibiotics for life Immunization against bloodborne pathogens 70 Secondary Lymphoid Tissue: Spleen Red pulp = contains red blood cells, macrophages, and some lymphocytes. Site where old and defective red blood cells are destroyed and removed. White pulp = Consists of B-cell follicles and the periarteriolar lymphoid sheath (PALS), which is populated by T lymphocytes. Marginal zone = specialized dendritic cells, macrophages, and unique MZ B cells. 72 Secondary Lymphoid Tissue: Barrier tissues Barrier tissues have secondary lymphoid environments too! MALT = Mucosa-associated lymphoid tissue Specialized: Gut-associated lymphoid tissue (GALT) Skin-associated lymphoid tissue (SALT) Nasal-associated lymphoid tissue (NALT) 73 Secondary Lymphoid Tissue: Barrier tissues Epithelial cells secrete cytokines, chemokines and antimicrobial compounds. Immune cells reside in deeper layers of the tissue. Mediate pathogen responses and maintain tolerance to commensal microbes. 74 Secondary Lymphoid Tissue: Barrier tissues M cells = specialized epithelial cells in GALT passing antigen from intestinal lumen to intestinal wall (lamina propria). B cell follicles and germinal centers form to produce plasma cells and antibodies. 75 Secondary Lymphoid Tissue: Barrier tissues Macrophages, DCs, Tregs and Intraepithelial lymphocytes (IELs) help distinguish pathogens from commensal microbes. Some of these immune cells can travel to a lymph node to generate a more systemic response. 76 Tertiary Lymphoid Structures Immune cells that recognize antigen in lymph nodes, return to organs (tertiary lymphoid tissue) as tissue-resident cells and form organized lymphoid structures. “Inducible lymphoid tissue” in response to chronic inflammation or cancer. Tertiary lymphoid structures in cancer, Volume: 375, Issue: 6576, DOI: (10.1126/science.abf9419) 77 78 79 Next week: Lecture 3 and Quiz 1 Date Jan 26th Lecture 3 Topic Innate Immunity Readings Chp 2,3 Due dates Quiz #1: 11:59AM 80