Adaptive Immune System Part 2 PDF

The Immunology & Infectious Adaptive Diseases – Session 3 Immune Ceinwyn Cooper cooperce@edgehil System – l.ac.uk Part 2 Outli ne T lymphocytes: T-cell maturation and the T-cell receptors Activation of and effector functions of...

The Immunology & Infectious Adaptive Diseases – Session 3 Immune Ceinwyn Cooper cooperce@edgehil System – l.ac.uk Part 2 Outli ne T lymphocytes: T-cell maturation and the T-cell receptors Activation of and effector functions of CD4 and CD8 cells, activation of B-cells Learning Outcomes: Discuss the maturation of T cells Discuss the structure of the T-cell receptor, and the role of the co-stimulatory molecules (including CD4 and CD8) Discuss important effector mechanisms involved in the protection against pathogens  Adaptive Immune System Cel Molecu ls les T- B- Solu Cell- Lymphocyt Lymphocyt ble Associat es es ed Receptor TC TH s B-cell (CD8 (CD4 Cytokines / +) Chemokine receptors +) s (BCR) Antibodies T-cell (humoral recept immune ors  The Cells of the Adaptive Immune System bone marrow haematopo lymphoid myeloid ietic Stem cells stem cell progenitor (progenitor) maturat ion and selectio n B cell T Bone marrow / cell Spleen Thym us bloo B and T d lymphocytes express antigen T cell recognition B (CD4, cell molecules (B CD8) and T cell  T-cell Development Overview  Produced in bone marrow Hematopoietic stem cells  Hematopoietic precursor  Thymus Thymocytes: T-cells undergoing maturation in the thymus  T-cell maturation in the thymus involves:  Rearrangement of the T-cell receptor (TCR)  Positive and negative selection (central tolerance): o Survival: Thymocytes bind to MHC I or MHC II molecules (+ve selection) o Apoptosis: Thymocytes strongly binding to self- peptides/ MHC I or MHC II complexes (-ve selection) Step 1 - Thymic Cortex Step 2 – Thymic Cortex Positive Selection Antigen presentation. Scanning electron micrograph (SEM) showing the interaction between a macrophage (right) and a T helper lymphocyte (Th cell, left), two components of the body's immune system. Both are types of white blood cell. Macrophages are antigen-presenting cells (APCs). They present antigens (fragments on the surface of pathogens or foreign objects) to T lymphocytes, activating them. Each T lymphocyte recognises and binds to a specific antigen. Binding of the Th cell to the antigen presented by the macrophage activates the Th cell. This leads to its proliferation and the activation of other immune cells that eliminate the antigen. Credit: Steve Gschmeissner/science Photo Library Step 3 - Thymic Medulla Negative Selection  Selection against T-cells that bind to self-antigens with high affinity  TCR’s identify which cells are foreign = Apoptosis  TCR’s identify which cells are ‘self’ and should be left alone Failure = Apoptosis or Step 4 – Thymic Medulla Single Positive Thymocytes  Double Positive Thymocytes bind to either MHC I or MHC II  CD4 bind to MHC II = T helper cell  CD8 bind to MHC I = T Cytotoxic cell  Regulatory/suppressor cells that regulate T-cell activity.  Mature T-cells move to lymphatic tissues  CD8 x MHC I CD4 x MHC II The Rule =8 =8 of 8 8x1 4x2 =8 =8 T-Cell Maturation: All these binding mechanisms are still unknown however these processes are some of the most complex in the human body. Remember! This binding is purely for the transfer of genetic information rather than form a permanent complex of joined molecules. Not all T cell bind successfully bind to MCHs. If T cells do not bind to Self-MHC it will die via FAS induced apoptosis i.e., programmed cell death. Only 2 – 5% of T-cells survive the full maturation process! https://youtu.be/JeV-HuPq7CI  Step 1: Thymic Cortex T-cells rearrange T-cell Overview receptor (TCR) genes in the thymus Expression of TCR’s Expression of both CD4 and CD8 receptors Double Positive thymocytes Positive and negative selection Step 2: Thymic Cortex Overvie Positive Selection w Thymic epithelial cells express self-MHC Selection for T-cells that bind to self- MHC If T-cells are unable to adequately bind = apoptosis If T-cells successfully bind = positive selection Double positive thymocytes Step 3: Thymic medulla Negative Selection Overview TCR antigen recognition is tested Failure = apoptosis or autoimmune disease risk Double positive thymocytes Step 4: Thymic medulla Single +ve Thymoscyte s Overview Generation of Single positive [either CD4 (T helper = TH) or CD8 (T cytotoxic = TC)] thymocytes All T-cells express TCR Move to lymph tissues ready for immune response Summary  The T-Cell Receptor (TCR) Structure Membrane-bound glycoprotein similar to the Fab fragment 2 polypeptide chains: α/β OR γ/δ 3 regions - variable (V) - constant (C) Fa - membrane-anchoring Recognises only protein b antigens presented on host F cells either by MHC I (TC cells / C CD8+) or MHC II (TH cells / CD4+)  Function of the T-Cell Receptor (TCR) Naïve T-cell (TCR) + APC (antigen on MHC I or II) signalling cascade … enhanced T-cell survival …. proliferation …. differentiation into distinct effector and memory Tc and TH subtypes  T Cell Subsets CD8 T-cells (Tc): recognise antigens on MHC I activation cytotoxic effector T cells destroy pathogen-infected cells CD4 T-cells (TH): recognise antigens on MHC II  activation activate CD8 and B cells - TH 1 secrete: IL-2 and IFN-γ (gamma) - TH 2 secrete: IL-4, IL-5, IL-6, IL- 10 and IL-13 - TH 17 secrete IL-17, IL-21 Lymphocyt e circulation and activation  Professional APC’s The professional APC present antigens on their surface using both MHC class I and MHC class II molecules  Antigen cross-presentation by dendritic cells Uptake by endocytosis of pathogenic particles and/or infected cells Simultaneous cross-presentation of pathogenic antigens on MHCI and MHC II  activation of TH (CD4+) and Tc (CD8+)  Mechanisms of T Cell Activation 1.Interaction of specific antigen: MHC complex with TCR supported by CD4 or CD8 co-receptors  Intracellular signalling  stabilisation of the connection MHC-TCR 2.Co- stimulat ion (only by professi onal APC): interac Proliferation and differentiation of T- Cells The activation of a T cell leads to the expression of interleukins (IL) and IL- receptors by the activated cell (autocrine activation) Proliferation and acquisition of effector function The effector cells are short lived – days to few weeks They can give rise to the long-lived memory cells Lymphocyte activation and differentiation Summary Role of Effector CD4 (TH1) cells TH1 cells secrete IL-2 and IFN-γ Activate macrophages with intra vesicular infections (e.g M. tuberculosis) by secreting IFN-γ IFN-γ induces secretion of TNFa by the macrophage =supports its viability and respiratory burst Activate Tc cells Activate B-cells to produce opsonising antibodies (e.g. IgG) classical complement activation  Role of Effector CD4 (TH2) cells  TH2 cells secrete IL-4, IL-5, IL-6, IL-10 and IL-13 help control infections by parasites via:  activating eosinophils and mast cells  switching B-cells to produce IgE antibodies Role of Effector CD4 (TH17 and TREG) cells TH17: secrete IL-17 and IL-21, stimulate neutrophils – help against extracellular bacteria and fungi  TREG: activate TH17 cells Subsets of CD4 effector T cells: Function  Activation of CD8 cells CD8 (Tc): defence against intracellular pathogens, especially viruses  2 mechanisms of CD8 activation: 1.Activation by mature dendritic cells (MHC class I)  IL-2  proliferation and activation 2. Activation with the help of CD4 cells: CD4 is induced to secrete IL-2  Role of Effector CD8 (TC) cells CD8 cells: kill target cells infected with viruses by apoptosis Break (20 mins)  Task 1 Choose 8 different parts of the immune system (cells, pathways, actions) Using your template fill in information about these 8 different sections of the immune system Include: 1) Speed of Activation Eosinophil 2) Length of Response 3) Pathogen Killing Power 4) Strength of 2nd immune response 5) Overall Immune Power Speed of 80 Activation Length of 2 Response Pathogen Killing 45 Power Strength of 2nd response 0 Overall Immune 40 Power  Task 2 Revision Questions We will go through the booklet at the end Adaptive immune response is launched when the innate immune system is overwhelmed Adaptive Immune Response Antibody T Cell- Mediated Mediated (Humoral) T cell- Activation Requires antigen B cell- Activation presentation No antigen presentation to B cell is required Effector and Memory Cells  Antibody-mediated immune response  The humoral immune response: Protects against extracellular pathogens in the body and on epithelial surfaces Prevents the spread of intracellular infections  The humoral immune response is initiated: Predominantly with the help of CD4 cells Directly by bacterial antigens e.g. polysaccharides, polymeric proteins and lipopolysaccharide Phases of an adaptive immune response Abbas AK, Lichtman AH (2011): Basic immunology: functions and disorders of the immune system, Ed 3, Philadelphia, Saunders  Exam Revision: Answer the following question 1. Describe the mechanisms of maturation and activation of T cells and their functions 2. List differences between B & T Cells – There are a lot! List as many as you can.  Relevant Reading J. Owen et al: Kuby Immunology 7th Edition, Chapters 11, 12. M. Murphy et al: Janeway’s Immunobiology; Chapters 3, 8, 9,10. P. Parahm: The Immune system 3rd Edition; Chapters 3, 5, 8, 9. Relevant chapters in Roitt’s Essential Immunology and Kuby: Immunology.