MCB 408 Lecture 6_ PRRs.pdf

9/16/24 MCB 408 Lecture 6 The innate immune system: Part 1 How do physical and molecular barriers protect each of us? How do we rapidly recognize a pathogen? Beth M. Stadtmuell...

9/16/24 MCB 408 Lecture 6 The innate immune system: Part 1 How do physical and molecular barriers protect each of us? How do we rapidly recognize a pathogen? Beth M. Stadtmueller, PhD Assistant Professor of Biochemistry Assistant Professor of Biomedical and Translational Sciences 1 2 1  9/16/24 Today’s Learning Objectives 1. Wrap up introduction to cytokines 2. Describe mechanisms of defense employed by the innate immune system 3. Understand how physical and chemical barriers function in innate immunity 4. Understand how Pattern Recognition Receptors (PRRs) detect pathogens and damage 5. Understand the role of Toll-like receptors (TLRs), their locations and the potential outcomes of their functions 3 Keywords Innate Response Skin Pathogen-associated molecular patterns (PAMPs) Pattern recognition receptors (PRRs) Anti-microbial compounds Psoriasin Lipopolysaccharide, endotoxin Toll-like receptors (TLRs) 4 2  9/16/24 Cytokine-receptor affinity (and thus function) can be regulated by receptor composition The interferon receptor family has 12 receptor chains that bind at least 27 different class 2 cytokines. Type I interferons (IFN-α and IFN-β) mediate early antiviral responses. Type II interferons (such as IFN-γ), which activate macrophages and support activation of adaptive immunity Type III interferons (IFN-λ) are secreted by plasmacytoid dendritic cells and regulate viral replication and host cell proliferation. 5 Tumor necrosis factor family bind and trimerize their receptors If downstream Example: TNF-α is a proinflammatory cytokine typically produced by activated macrophages and lymphocytes. 6 3  9/16/24 Inhibiting cytokines is a therapeutic strategy for regulating immune response Humira (Adalimumab) is a monoclonal antibody that works by inactivating tumor necrosis factor- alpha (TNFα) Immunosuppressive -> treats autoimmune diseases $20 Billion in annual sales 7 (Optional) Monoclonal antibodies to treat cancer Immunology wars: Monoclonal antibodies https://www.youtube.com/watch?v=5AXApBbj1ps&feature=youtu.be 8 4  9/16/24 IL-17 cytokines identified in the past 30 years Like TNF cytokines The IL-17 family of cytokines are typically proinflammatory. some secreted by T helper 17 cell Typically secreted as dimers IL-17 family receptors may be dimeric or trimeric Homo or hetero oligomeric receptor complexes 9 Chemokines provide signals for cell mobility move towards chemical 10 cytokine that acts on chemokine receptorGPCR 5  9/16/24 Chemokines provide signals for cell mobility Chemokines act on G protein–coupled receptors to promote the movement of immune system cells into, within, and out of lymphoid organs. 11 Chemokines provide signals for cell mobility Chemokines act on G protein–coupled receptors to promote the movement of immune system cells into, within, and out of lymphoid organs. Chemokines are classified by a structural signature Chemokine names include “L” (ligand) and receptor names include “R”(Receptor) For example, CXCL12 is a chemokine that can attract lymphocytes (e.g. T cells) and binds receptor CXCR4 Chemokine receptors can be utilized by Notalways pathogens } FifiL CXCR4 HIV co-receptors CCR5 CD4 and chemokine receptors on TH cells can facilitate HIV-1 entry into the cell. ok these t.si in 12 Spike proteins farapart Hard tobind cooperatively 6  9/16/24 Be patient and remember that learning cytokines and their receptors is like learning a new language. We will learn cytokines (and the message they deliver) on a case-by-case basis. Case Case by Basis Know Families and what Cytokines Can do 13 Conclusions: Molecular interactions are fundamental to antigen-specific (adaptive) interactions as well as receptor- ligand that transmit communication between cells and transduce signals cells. As exemplified by BCR-antigen and cytokine-receptor interactions, receptor-ligand affinity, avidity and signaling can be modulated or “tuned” in many ways to regulate immune responses. Up next: Innate Immunity; PRRs 14 7  9/16/24 The innate immune system provides rapid protective responses by employing barrier mechanisms, simple biochemical defenses, and cellular responses while also initiating adaptive immune responses 15 2. Innate Response Begins. Phagocyte detects invader via a molecular pattern and releases 4. T cells and B cells from the molecules that promote blood stream intersect inflammation pathogen in lymph node 3. Pathogen and Phagocyte migrate through the lymphatic vessels 1. Innate barrier is breached by pathogen to lymph node 5. Adaptive Response Begins T cells e and B cells that can bind this pathogen undergo differentiation and proliferation (Clonal Selection:) 7. T and B cells and antibodies migrate to the sites of infection and eliminate any remaining pathogen 6. Specialized T and B cells and antibodies that can bind the pathogen join the bloodstream and are pumped though the body 8. Memory T and B cells remain in the body in case this pathogen is encountered again Adapted from 16 8  9/16/24 Remember, the innate immune response is rapid Way better during 2nd infection Same Response always 17 Innate barriers are extensive, diverse and dynamic. ij golf specific Physicalmechanisms are importantCoughing Expelling flowof FluidMuscleContractions Muers 18 9  9/16/24 Innate barriers include molecular barriers 8 I 19 of Why? Psoriasin Innate barriers include molecular barriers L 20 10  9/16/24 2. Innate Response Begins. Phagocyte detects invader via a molecular pattern and releases 4. T cells and B cells from the molecules that promote blood stream intersect inflammation pathogen in lymph node 3. Pathogen and Phagocyte migrate through the lymphatic vessels 1. Innate barrier is breached by pathogen to lymph node 5. Adaptive Response Begins T cells and B cells that can bind this pathogen undergo differentiation and proliferation (Clonal Selection:) 7. T and B cells and antibodies migrate to the sites of infection and eliminate any remaining pathogen 6. Specialized T and B cells and antibodies that can bind the pathogen join the bloodstream and are pumped though the body 8. Memory T and B cells remain in the body in case this pathogen is encountered again Adapted from 21 Cellular responses to pathogens begin by binding to invaders 0 signal to IS stone 14 Remit NKtell Key Concept: Molecules on your cells are different than molecules on a pathogen’s cells. 22 11  9/16/24 How do cells know what is a pathogen? Molecules on our 101 surface differs from those on pathogens 23 How does this cell know this is a pathogen and how is it able to engulf it? Pathogens are different than their hosts (self is different than non-self). PRR's on Pathogens have molecular signatures that we don’t have and they can be harmed by things that don’t* harm us. Dendritic cells and Pattern recognition receptors (PRR) on immune cells interact with molecules typically found on microbes called pathogen-associated molecular patterns; PAMPs) Macrophages PAMP's 24 Note We are so good at responding to LPS we are our own wis get the12 different molecular affair To s  I 5 PRRs 9/16/24 look for Pattern recognition receptors (PRR) on immune cells interact with molecules typically found on microbes (pathogen-associated molecular patterns; PAMPs) PAMP PRR 25 There are many molecularly distinct PAMPS and accordingly, many families of PRRs that that have evolved to recognize them. PRR E E …location, location, location iii 26 13  9/16/24 Example: Dendritic cell PRR functions linking innate and adaptive immune responses if on Pathogen Dendriti Cell 27 PRRs are found in virtually ALL plants and animals Everything PRRE PRR's are very old evolutionarily 28 14  9/16/24 Pattern recognition receptors (PRR) on immune cells interact with molecules typically found on microbes (pathogen-associated molecular patterns; PAMPs) 29 TLRs are located on plasma membranes or endosomal membranes and function as dimers. TLRs detect 1 CanPhete or homodimers PS 30 15  9/16/24 TLRs are located on plasma membranes or endosomal membranes and function as dimers. Lipopolysaccharide (LPS) Endotoxin is a common TLR ligand (PAMPs) 31 TLRs have leucine-rich repeats (LRRs) and dimerize (homo or hetero) upon binding ligand. PAMP hdesprouffffiaf.ie Note All TLRs look similarbut “Toll-like or IL-1 Receptor domain” 5 this Down stream signaling is initiated by the TIR domains, which can adaptors are either MyD88 or TIR “adaptor” proteins. 32 16  9/16/24 Activation of TLRs includes the use of adaptor proteins that influence which transcription factors are upregulated and thus, the immune response Diff PAMP lead to activation andactivate Ap MAP kinase had iii signal transduction pathifays Activate diffgenes pathway 33 Antiviralresponses snRNAand dsRNA or involved in hallmark of viruses a Activation of TLRs includes the use of adaptor proteins that influence which transcription factors are upregulated and thus, the immune response 34 17  9/16/24 TLRs are located on plasma membranes or endosomal membranes and function as dimers. Lipopolysaccharide (LPS) Endotoxin is a common TLR ligand (PAMPs) There are other proteins that help TLRs bind ligands and activate them 35 Toll-like receptor 4 signaling 36 18  9/16/24 Some bacterial species change the O-antigen they express. How might this influence a TLR versus antibody response to LPS? O-antigen figure Adapted from Yagmur Turgay (ETH Zurich) 37 Some bacterial species can change the O-antigen they express. How might this influence a TLR versus antibody response to LPS? O-antigen figure Adapted from Yagmur Turgay (ETH Zurich) 38 19  9/16/24 Some bacterial species can change the O-antigen they express. How might this influence a TLR versus antibody response to LPS? TLRs functions recognizes common features of most LPS (rapidly) whereas an antibody response will be specific for a particular O antigen. It will take time to develop a new antibody for a new O-antigen sequence! O-antigen figure Adapted from Yagmur Turgay (ETH Zurich) 39 Example: Dendritic cell PRR functions linking innate and adaptive immune responses 40 20  9/16/24 Example: Dendritic cell PRR functions linking innate and adaptive immune responses Next time we will discuss other families of PRRs 41 Conclusion: The the innate immune system provides barriers and can recognize non-self pathogens and turns that recognition into action. The functions of TLRs exemplify this process. Up next: More PRRs and their downstream actions, phagocytes and NK cells 42 21