Cells of the Immune System and Antigen Recognition Jennifer Nyland, PhD Office: Bldg#1, Room B10 Phone: 733-1586 Email: jnyland@uscmed.sc.edu Teaching objectives • To review the role of immune cells in protection from different types of pathogens • To discuss the types of cells involved in immune responses • To describe the nature of specificity in adaptive immune responses • To understand the role of lymphocyte recirculation in immune responses Overview of the immune system • Purpose: – Protection from pathogens • Intracellular (viruses, some bacteria and parasites) • Extracellular (most bacteria, fungi, and parasites) – Eliminate modified or altered “self” • Cancer or transformed cells • Sites of action: – Extracellular – Intracellular Overview- extracellular pathogens • Ab are primary defense – Neutralization – Opsonization – Complement activation Overview- intracellular pathogens • Cell-mediated responses are primary defense – Ab are ineffective – Two scenarios: • Pathogen in cytosol – Cytotoxic T cell (CD8) • Pathogen in vesicles – Th1 (CD4) releases cytokines – Activates macrophages Cells of the immune system Immune system Myeloid cells Lymphoid cells Granulocytic Monocytic T cells Neutrophils Macrophages Helper cells Basophils Kupffer cells Suppressor cells Eosinophils Dendritic cells Cytotoxic cells B cells Plasma cells NK cells Development of the immune system Stem cell T cell Granulocyte Myeloid progenitor Lymphoid progenitor NK cell Mast cell B cell Monocyte Macrophage Dendritic cell Plasma Cell Cells of the immune system Eosinophil Lymphocyte (T, B, NK) Plasma cell Basophil Granular Agranular (35% in circulation) Monocyte Neutrophil Dendritic cell Phagocytosis and Intracellular killing Neutrophils and Macrophages Phagocytes – neutrophils (PMNs) • Characteristic nucleus, cytoplasm • Granules • CD66 membrane marker protein Neutrophil Geimsa stain Source: www.dpd.cdc.gov Characteristics of neutrophil granules Primary granules Secondary granules Azurophilic; young neutrophils Specific for mature neutrophils Contain: cationic proteins, lysozyme, defensins, elastase and Contain: Lysozyme, NADPH oxidase components and myeloperoxidase Lactoferrin and B12-binding protein Phagocytes – macrophages Macrophage Source: Dr. Peter Darben, Queensland University of Technology, used with permission • Characteristic nucleus • lysosomes • CD14 membrane marker protein Non-specific killer cells NK cells Eosinophils Natural killer (NK) cells • Also known as large granular lymphocytes (LGL) • Kill virus-infected or transformed cells • Identified by the CD56+/CD16+/CD3• Activated by IL-2 and IFN-γ to become LAK cells Eosinophils • Characteristic bi-lobed nucleus • Cytoplasmic granules, stain with acidic dyes (eosin) – Major basic protein (MBP) – Potent toxin for helminths Source: Bristol Biomedical Image Archive, used with permission • Kill parasitic worms Mast cells Source: Wikimedia • Characteristic cytoplasmic granules • Responsible for burst release of preformed cytokines, chemokines, histamine • Role in immunity against parasites Cells of the immune system: innate • Phagocytes – Monocytes/macrophages – PMNs/neutrophils • • • • NK cells Basophils and mast cells Eosinophils Platelets Cells of the immune system: APC • Cells that link the innate and adaptive arms – Antigen presenting cells (APCs) • Heterogenous population with role in innate immunity and activation of Th cells • Rich in MHC class II molecules (lec 11-12) – Examples • • • • Dendritic cells Macrophages B cells Others (Mast cells) Cells of adaptive immune response T cells and B cells Cells of the immune system: adaptive • Lymphocytes – B cells • Plasma cells (Ab producing) – T cells • Cytotoxic (CTL) • Helper (Th) – – – – Th1 Th2 Th17 T-reg Major distinguishing markers Marker B cell CTL T-helper Antigen R BCR (surface Ig) TCR TCR CD3 -- + + CD4 -- -- + CD8 -- + -- CD19/ CD20 + -- -- CD40 + -- -- Specificity of adaptive immune response • Resides with Ag R on T and B cells • TCR and BCR – both specific for only ONE antigenic determinant • TCR is monovalent • BCR is divalent T cell B cell TCR BCR Ag Specificity of adaptive immune response • Each B and T cell has receptor that is unique for a particular antigenic determinant on Ag • Vast array of different AgR in both T and B cell populations • How are the receptors generated? – Instructionist hypothesis • Does not account for self vs non-self – Clonal selection hypothesis • AgR pre-formed on B and T cells and Ag selects the clones with the correct receptor Four principles of clonal selection Hθ 1. Each lymphocyte has a SINGLE type of AgR 2. Interaction between foreign molecule and AgR with high affinity leads to activation 3. Differentiated effector cell derived from activated lymphocyte with have the same AgR as parental lymphocyte (clones) 4. Lymphocytes bearing AgR for self molecules are deleted early in lymphoid development and are absent from repertoire Specificity of adaptive immune response • Clonal selection Hθ can explain many features of immune response – Specificity – Signal required for activation – Lag in adaptive immune response – Discrimination between self and non-self Development of the immune system Bone Marrow Tissues Thymus Stem cell Granulocyte T cell Myeloid progenitor Lymphoid progenitor NK cell Mast cell B cell Monocyte 2° Lymphoid Macrophage Dendritic cell Plasma Cell Lymphocyte recirculation • Relatively few lymphocytes with a specific AgR – 1/10,000 to 1/100,000 • Chances for successful encounter enhanced by circulating lymphocytes – 1-2% recirculate every hour Lymphocyte recirculation • Lymphocytes enter 2° lymphoid organs via high endothelial venules (HEVs) • Ag is transported to lymph nodes via APC • Upon activation, lymphocytes travel to tissues Bone marrow Thymus T cell T cell B cell B cell DC T cell Virgin lymphocytes B cell Spleen and lymph nodes Primed lymphocytes T cell B cell Monocyte APC Tissues Lymphocyte recirculation • After activation, new receptors (homing R ) are expressed to direct to tissues • R on lymphocytes recognize CAMs on endothelial cells • Chemokines at infection help attract activated lymphocytes Bone marrow Thymus T cell T cell B cell B cell DC T cell Virgin lymphocytes B cell Spleen and lymph nodes Primed lymphocytes T cell B cell Monocyte APC Tissues