Immunology Lecture 4 2023 PDF

DMED 511 - Immunology Lecture 4 Cell Mediated Immunity and Cytokines Sneha Suresh MD, FRCPC / [email protected]  Specific Learning Objectives for this Lecture 1. Describe how the cell mediated immune response gets activated and responds to intracellular pathogens. 2. Describe the role of...

DMED 511 - Immunology Lecture 4 Cell Mediated Immunity and Cytokines Sneha Suresh MD, FRCPC / [email protected]  Specific Learning Objectives for this Lecture 1. Describe how the cell mediated immune response gets activated and responds to intracellular pathogens. 2. Describe the role of a natural killer cell in the immune system 3. Describe the roles of cytokines in the immune system 4. Describe the general properties of pleiotropy, redundancy, synergy and antagonism. 5. Describe one major property of 6 cytokines on the cytokine short list. Lecture 1 - The Innate Immune System Inflammatory Response Lecture 2 - Antigen Presentation & T helper cell differentiation Lecture 2 - Antigen Presentation & T helper cell differentiation *Lecture 2 Recall: Mature Effector TH cells are required for many immune functions : antibody production, activations of macrophages and CD8+ T cells (CTLs)  In the lymph node Primed B cell Lecture 3 - B cells and Antibodies Primed T cell Lecture 3 - B cells and Antibodies Neutralization! Opsonization! Complement Activation! ADCC! Some threats are inside the cell! How does our body deal with internal (intracellular) threats? 1. Cytotoxic Cells: - CD8+ Cytotoxic T cells - Natural Killer Cells 2. Cytokines: - TNF - alpha - IFN – gamma - DTH Response 1. If the problem is something internal, like a cell getting infected by a virus the immune system’s best strategy is to kill the infected cell. 2. Viral proteins will get made inside the cell, and some of these will be degraded into peptides. 3. The viral peptides will get displayed on the MHC class I, and CD8 cells with the ‘right fit’ TCR can then come and kill the cell. CD8+ T cell activation 1. CD4+ T cells or other pathogenic proteins “license” dendritic cells to be able to activate CD8+ 2. Naïve CD8+ cells then become primed to be cytotoxic T cells (CTLs) Cytotoxic T cell Action 1. MHC class I is present on all cells with a nucleus. Cells can tell activated T cells that they are in danger and should be “killed” 2. Activated effector CTL’s only require their ‘right fit’ MHC Class I holding their ‘right fit’ peptide (e.g. viral) to kill. 3. Each CTL can kill multiple targets-- they move along killing one infected cell after another. They will leave adjacent uninfected cells alone--only infected cells are killed. 4. CTL kills via apoptosis there is no non-specific inflammation and no harm to adjacent uninfected cells Cytotoxic Cell Death → A quiet cell death Necrosis Apoptosis Caused by some kind of A natural process which occurs mechanical, thermal, or throughout life chemical insult (or ‘Programed cell death’ alternately by abrupt loss of blood flow to a tissue) the dead cell is removed without triggering any Direct release of inflammation intracellular contents and intracellular contents “bleb” off leads to inflammation. CTL killing → multiple ways to induce apoptosis 1. Perforin/Granzyme: - The CTL attaches to its target, secretes some perforin into the space between the cells - perforin polymerizes to form a transmembrane pore in the target cell - granzymes from the CTL move into the target cell through these pores - granzymes are proteases that activate caspases within the target cell to induce apoptosis 2. Fas Ligand on target cell 3. Cytokine - TNF beta aka lymphotoxin Viruses are sneaky – many make proteins to inhibit the Class I MHC expression Natural Killer Cells – Primed -and Ready to Kill 1. Antibody dependent cellular cytotoxicity Antibodies bound on the surface of the target, then binding to Fc gamma receptors on NK cells KAR (lecture 3) 1. Killer inhibitory receptors’ (KIRs) and ‘killer activating receptors’ (KARs) The KIRs bind to MHC class I molecules and are constantly ‘checking that the MHC’s are there’. As long as the KIRs are getting a signal, killing is KAR inhibited—the KARs can be engaged, but the KIR signal is dominant. When viruses or tumors prevent MHC class I from getting to the cell surface—in this case the KIRs fail to get a signal, the KARs are no longer suppressed, and the target is killed. How does our body deal with internal (intracellular) threats? 1. CD4+ Helper T Cells: - Th1 Cells 2. Cytotoxic Cells: - CD8+ Cytotoxic T cells - Natural Killer Cells 3. Cytokines: - TNF - alpha - IFN – gamma - DTH Response What are cytokines? 1. Cytokines are small soluble proteins that simulate the proliferation and/or differentiation of immune cells 2. Most have the name ‘interleukin’ followed by a number (eg. IL-2, IL-4, etc.)but interferon gamma (IFN- g) and tumor necrosis factor alpha (TNF-a) are other examples. 3. They are sort of like hormones, but tend to signal very locally (just to nearby cells). - Pleiotropy - A single cytokine may be able to act on different kinds of cells, possibly even causing different effects - Redundancy - A few different cytokines may be able to all cause the same effect (e.g. make B cells proliferate). - Synergy - Certain combinations of cytokines can cause effects that neither by itself could induce - Antagonism - Some cytokines can block the effects of other cytokines; this allows for reciprocal regulation (e.g Th1 vs Th2). How does our body deal with internal (intracellular) threats? 1. Mycobacterium tuberculosis is ingested by APCs in the lung (alveolar macrophages). 2. TB bacteria evade phagocytosis and live/grow/hide out in the macrophages 3. Antibody/CTL responses are not effective in clearing the pathogen Delayed Type Hypersensitivity Response Cytokines act on the macrophage itself can help “activate” the infected macrophage deal with its pathogen.  1. 1. Macrophage becomes infected 2. Activated effector anti-TB Th1 cells can recognize that the cell is infected (TCR sees TB 2. peptide+MHC) and secretes IFN-g. 3. The IFN-g activates the infected 3. macrophage 4. TNF-alpha receptors increase, TNF alpha binds 5. Macrophage becomes a super- killing macrophage 4.  1. Sometimes the anti-TB response is not able to clear every infected macrophage 2. The remaining cells are walled off and a granuloma is formed 3. Granuloma is maintained by activated macrophages, Th1 cells and cytokines – importantly TNF alpha TNF alpha 4. If these functions remain intact, granuloma maintained for life (latent TB infection)  TNF alpha inhibitors are manufactured antibodies that bind TNF alpha Potent immunosuppressive drug Used in Crohns disease, rheumatoid arthritis ***Must Rule Out Latent TB Infections*** Cytokines are important all along the immune response  - IL-1 - TNF-alpha Inflammatory Response - IL-6  1. After successful costimulation by an APC, a TH cells makes many identical daughter cells → Clonal Selection 2. The daughters then differentiate into mature effector TH cells, different types of TH cells promote different types of immune responses 3. Mature Effector TH cells are IL-2 required for many immune functions : antibody production, activations of macrophages and CD8+ T cells (CTLs) 4. Some become long lasting *IL-2 = interleukin 2 a cytokine that memory T cells makes T cells grow. What controls TH differentiation? - Signalling Molecules called Cytokines c - Depending on the types of cytokines made, different kinds of immune responses are induced.  IL-4 the key Th2 cytokine  IFN-g the key Th1 cytokine Cytokines to remember Cytokine Functions Mnemonic IL-2 A T cell growth factor, also made by Th1 cells and enhances CTLs, T2 NK cells IL-4 Key Th2 cytokine, made by Th2 cells, costimulates activation of There are 4 antibody antigen-primed B cells, stimulated proliferation and differentiation classes of B cells, class switching to IgG1 and IgE IFN-g Key Th1 cytokine, made by Th1 cells, increases MHC expression, GranulomA blocks IL-4 induced class switch to IgE, inhibits proliferation of Th2 cells, promotes formation of super-macrophages in DTH IL-10 Key Th2 cytokine which inhibits Th1 responses, made by Th2 aTENtion cells and macrophages IL-17 Key TH17 cytokine, recruits and activates neutrophils 17 yo’s get acne TNF-a Made by macrophages in inflammatory response, works with GranulomA IFNg for DTH response, maintains granulomas  Cytokine Inhibition is powerful way to suppress the immune system TNF alpha inhibitors are manufactured antibodies that bind TNF alpha → Crohns disease, rheumatoid arthritis IL17 inhibitors →psoriasis IL-6 inhibitors → severe COVID, hyperinflammatory states  Specific Learning Objectives for this Lecture 1. Describe how the cell mediated immune response gets activated and responds to intracellular pathogens. 2. Describe the role of a natural killer cell in the immune system 3. Describe the roles of cytokines in the immune system 4. Describe the general properties of pleiotropy, redundancy, synergy and antagonism. 5. Describe one major property of 6 cytokines on the cytokine short list.