Kuby Immunology EIGHTH EDITION

Kuby Immunology EIGHTH EDITION
Punt • Stranford • Jones • Owen Kuby Immunology EIGHTH EDITION Lecture PowerPoint CHAPTER 3 Recognition and Response Edited by TPF: Sept. 23, 2018 Copyright © 2019 by W. H. Freeman and Company

Topics Marked in Red are Covered in this first third of BIO 447
How Chapter 3 in Kuby 8th Edition is Organized: Recognition and Response Slides 2 to 23 Topics Marked in Red are Covered in this first third of BIO 447 (Slides 1, 3 to 6, and 8 to 16) Slides 2 and 7 Cytokine Signaling Slides 3, 4, 5, 6 Ligand-Receptor Interactions Slides 8, 9, 10 Antigen Receptors (Antibodies and T-Cell Receptors) Slides Structure of Antibodies Dimeric Structure of Antibodies Immune Antigen Receptor Molecules: Antibody Antibody Isotypes B-Cell Antigen Receptors Slides 17 – 21 T-Cell Receptor and Antigen Presentation and Binding Slides 22 and 23 Pathogen-Associated Molecular Pattern Receptors Slides 24 and following Cytokine Signaling

T Lymphocytes (blue) stimulated by specific antigen up-regulates IL2 Cytokine
receptor (yellow) increasing response of those antigen-specific T-cells to IL2

Common Features of Receptor-Ligand Interactions
Receptor-ligand binding occurs via multiple noncovalent bonds Each individual bond may be weak but in total deliver a strong binding affinity Many such bonds occur between receptors and ligands, providing great cumulative bond strength Dissociation constant (Kd) is a measure of strength of ligand binding

Receptor-ligand interactions may be multivalent Multivalency increases avidity of the interactions Individual interactions have an affinity, the strength of an individual bond Avidity is the combined strength of binding of multiple interactions An interaction may have weak affinity but high overall avidity

Ligand-receptor binding induces molecular change in the receptor Conformational Dimerization/clustering Location in the membrane Covalent modification Receptor alterations induce cascades of intracellular events Activation of enzymes Changes in intracellular locations of molecules

Common Features of Immune Receptor-Ligand Interactions
Aggregation due to ligand binding enhance ligand binding Kd Cell-cell interactions rely on a binding affinity to maintain contact over long periods of time Extended contact facilitates signal transduction and exchange of cytokine signals Cytoskeletal reorganization may occur upon extended binding

Dendritic cell (Blue) with specifically bound T-cell (Green) produces activating cytokine IL12 (pink) and showers bound T-cell with the activating cytokine

Common Features of Immune Receptor-Ligand Interactions
Immune Receptors bear immunoglobulin domains Immune Receptors can be transmembrane, cytosolic, or secreted Immunoglobulin lacking the carboxyl terminus transmembrane segment is secreted

Immune Antigen Receptor Molecules
B-cell Receptor (BCR) contains an antibody of defined specificity T-cell receptor (TCR) specificity is for peptides derived from APC degraded antigen presented on MHC molecules CD4 and CD8 are T-cell coreceptors that define different subsets of T-cell function

Immune Antigen Receptor Molecules Antibody
A quaternary protein with two identical heavy chains and two identical light chains Antigen specificity is by the interaction between light/heavy chain variable regions Antibody effector activity, e.g., phagocytosis and complement fixation, is a function of the interaction of the constant regions of the heavy chain

Three hypervariable regions of amino acids are found in variable heavy (VH) and variable light (VL) regions These regions come together to form the antibody combining site These regions are known as complementarity-determining regions known as CDR1, CDR2, and CDR3 in VH and VL Interspersed near each CDR is an invariant amino acid that forms the framework region and is responsible for the folding of the CDRs to form the antibody combining site

Antibody V-region binding to Target Antigen Influenza Hemagglutinin Antigen shown in blue oval X-ray Crystallographic Stucture

Antiserum to the constant region of the heavy chain identifies five distinct classes of antibody called isotypes IgA: alpha (α) heavy chain IgD: delta (δ) heavy chain IgE: epsilon (ε) heavy chain IgG: gamma (γ) heavy chain IgM: mu (μ) heavy chain Light chain isotypes are Kappa (κ) Lambda (λ)

Antibody molecules form a B- cell receptor (BCR) complex with molecules involved in signal transduction Igα, Igβ: transduce signals via ITAMs CD19, CD81, CD21: transmit and relay signals to cell interior

Immune Antigen Receptor Molecules T-Cell Receptor
Structurally similar to immunoglobulin domains Two subunits, α and β, each have a Constant region and Variable region Variable regions have three CDRs forming peptide specific binding site Constant regions each contain transmembrane regions Two TCR types, αβ and γδ, have diverse antigen binding characteristics

TCR recognizes and binds both antigen-derived peptide and MHC to which peptide is bound Peptide sources can be from endogenously or exogenously processed antigens

FUNCTION: Signal transduction FUNCTION: Member of Ig superfamily
Table 3-1, Selected T-cell accessory molecules participating in T-cell signal transduction, Page 88 Name Ligand FUNCTION: Adhesion FUNCTION: Signal transduction FUNCTION: Member of Ig superfamily CD4 Class II MHC + CD8 Class I MHC CD2 (LFA-2) CD58 (LFA-3) CD28 CD80, CD86 ? CTLA-4 − CD45R CD22 CD5 CD72

The T-cell receptor (TCR) complexes with coreceptor involved in antigen recognition CD3 contains ITAMs that transmit signal to cell CD4, CD8 function in increasing avidity of peptide binding by TCR CD28 engages CD80 or CD86 on APC to fully activate a naive T cell

Immune Antigen Receptor Molecules PAMPs
Pathogen Associated Molecular Patterns (PAMPs) Receptors for PAMPs may uniformly recognize large numbers of bacteria that share the same PAMPs Receptors for PAMPs are not clonally distributed but are expressed equally on the same cell types Receptors for PAMPs may be integral membrane proteins or intracellular proteins PAMPs represent motifs of recurring patterns on bacteria, yeast, and parasites

Table 3-2, Pattern recognition receptor families, Page 91
Full name Cellular location(s) Ligands Cellular functions TLR Toll-like receptor Plasmamembrane, endosomes, Lysosomes Microbial carbohydrates, lipoproteins, fungal mannans, bacterial flagellin, viral RNA, self-components of damaged tissues, etc. Production of antimicrobials, antivirals, and cytokines; inflammation CLR C-type lectin receptor Plasma membrane Carbohydrate components of fungi, mycobacteria, viruses, parasites, and some allergens Phagocytosis, production of antimicrobials and cytokines; inflammation RLR Retinoic acid inducible gene-I (RIG-I)-like receptor Cytosol Viral RNA Production of interferons and cytokines NLR Nucleotide oligomerization domain (NOD)-like receptor Fragments of intracellular or extracellular bacteria cell wall peptidoglycans Production of antimicrobials and cytokines; inflammation ALR Absent-in-melanoma (AIM)-like receptor Cytosol and nucleus Viral and bacterial DNAs

Cytokines and their receptors
Cytokine signals are usually generated by the binding of a ligand to a complementary cell-bound receptor Cytokine-receptor binding is noncovalent, although it may be of generally high affinity Cytokine-signaling end results often induce a change in the transcriptional program of the target cell A cytokine signal is any event that instructs a cell to change its metabolic or proliferative state

General properties of cytokines and chemokines
Cytokines are proteins that mediate the effector functions of the immune system They can act in several different ways… Endocrine action ‒ released into the bloodstream to effect distant cells Paracrine action ‒ released to effect nearby cells Autocrine action ‒ released, but then bind to receptors on the cell that produced them

General properties of cytokines and chemokines
Pleiotropic activity induces different biological effect dependent on target cell Redundant activity mediates similar effects on target cell Synergy effect combines two cytokine activities to be greater than additive effect Antagonistic effect inhibits one cytokine’s effect by another’s action Cascade effect of one cytokine on one target cell to produce additional cytokine(s)

Cytokine Classes and their Actions
Cytokines of the IL-1 family promote inflammation IL-1 stimulated by viral, parasitic, or bacterial antigens Secreted very early in immune responses by macrophages and dendritic cells Acts locally on capillary permeability and to pull leukocytes to infected tissues Acts systemically to signal the liver to produce acute phase proteins Can help to activate adaptive immune responses

Table 3-3, The six major cytokine families, Page 92
Family name Representative members of family Comments Interleukin-1 family IL-1α, IL-1β, IL-1Ra, IL-18, IL-33 IL-1 was the first noninterferon cytokine to be identified. Members of this family include important inflammatory mediators. Class 1 (hematopoietin) cytokine family IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-12, IL-13, IL-15, IL-21, IL-23, GM-CSF, G-CSF, growth hormone, prolactin, erythropoietin/hematopoietin Members of this large family of small cytokine molecules exhibit striking sequence and functional diversity. Class 2 (interferon) cytokine family IFN-α, IFN-β, IFN-γ, IL-10, IL-19, IL-20, IL-22, IL-24 While the IFNs have important roles in antiviral responses, all are important modulators of immune responses. Tumor necrosis factor family TNF-α, TNF-β, CD40L, Fas (CD95), BAFF, APRIL, LT-β Members of this family may be either soluble or membrane-bound; they are involved in immune system development, effector functions, and homeostasis. Interleukin-17 family IL-17 (IL-17A), IL-17B, IL-17C, IL-17D, IL-17F This is the most recently discovered family; members function to promote neutrophil accumulation and activation, and are proinflammatory. Chemokines (see Appendix III) IL-8, CCL19, CCL21, RANTES, CCL2 (MCP-1), CCL3 (MIP-1α) All serve chemoattractant function.

Cytokine classes and their actions
Class I cytokines are diverse in action and cell target Structurally class I cytokines are a single protein family Most of class I cytokines are made up of multiple subunits

Common cytokine receptor subunit
Table 3-4, Common subunits of class 1 family cytokine receptor subfamilies, Page 95 Common cytokine receptor subunit Cytokines recognized by receptors bearing that common subunit γc IL-2, IL-4, IL-7, IL-9, IL-15, IL-12 βc IL-3, IL-5, GM-CSF gp130 IL-6, IL-11, LIF, OSM, CNTF, IL-27

Interferon (IFN) Class II cytokine family Type I interferons IFN-α and IFN-β are 18–20 kDa dimers with antiviral effects Secreted by activated macrophages and dendritic cells Induce synthesis of ribonucleases and inhibit protein synthesis Type III interferon family (IFN-λ) Secreted by plasmacytoid dendritic cells Upregulate genes controlling viral replication and host cell proliferation

Interferon (IFN) Class II cytokine family Type II interferon (IFN-γ) Dimer produced by activated T/NK cells Potent modulator of adaptive immunity

Interferon (IFN) Class II cytokine family Type III interferon family (IFN-λ) Secreted by plasmacytoid dendritic cells Upregulate genes controlling viral replication and host cell proliferation

Tumor Necrosis Factor (TNF) regulates development, effector function, and homeostasis of cells of the skeletal, neuronal, and immune system TNF cytokines may be soluble or membrane bound Short intracytoplasmic N-terminal regions Longer extracellular C-terminal region Generally Type 2 transmembrane proteins form as trimers when binding to TNF receptor-1

TNF-α is proinflammatory and produced by activated macrophages and other cell types TNF-β (lymphotoxin-α) is produced by activated lymphocytes, delivering signals to leukocytes and endothelial cells Five membrane-bound TNF members Lymphotoxin-β: lymphocyte differentiation BAFF and APRIL: B-cell development and homeostasis CD40 Ligand (CD40L): T-cell differentiation signal to B cell Fas Ligand (FasL): induces cell death (apoptosis) upon ligand binding

IL-17 family cytokines are proinflammatory molecules expressed on a variety of cells Receptors found on neutrophils, keratinocytes, and other nonlymphoid cells Tend to work at the interface of innate and adaptive immunity Generally exist as homodimers Monomers range from 17.3–22.8 kDa All are transmembrane proteins

Cell types expressing cytokines of the IL-17 family
Table 3-5, Expression and known functions of members of the extended IL-17 cytokine family, Page 98 Family member Other common names Receptor(s) Cell types expressing cytokines of the IL-17 family Main function(s) IL-17A IL-17 and CTL-8 IL-17RA and IL-17RC TH17 cells, CD8+ T cells, γδ T cells, NKT cells, LTi-like cells, neutrophils, Paneth cells Induces expression of proinflammatory cytokines, neutrophil recruitment, and antimicrobial peptide induction; promotion of T-cell priming and antibody production IL-17B NA IL-17RB Chondrocytes, neurons Induces expression of proinflammatory cytokines and neutrophil recruitment IL-17C IL-17RE TH17 cells, DCs, macrophages, keratinocytes IL-17D Unknown TH17 cells, B cells Proinflammatory cytokine production IL-17E IL-25 IL-17RA and IL-17RB TH17 cells, CD8+ T cells, mast cells: eosinophils, epithelial cells, endothelial cells Induces TH2 and TH9 responses; suppresses TH1 and TH17 responses; eosinophil recruitment IL-17F TH17 cells, CD8+ T cells, γδ T cells, NK cells, NKT cells, LTi-like cells, epithelial cells Neutrophil recruitment and immunity to extracellular pathogens; induces expression of proinflammatory cytokines Data from Gaffen, S. L Structure and signalling in the IL-17 receptor family. Nature Reviews Immunology 9:556; and Iwakura, Y., H. Ishigame, S. Saijo, and S. Nakae Functional specialization of interleukin-17 family members. Immunity 34:149.

Chemokine classes and their actions
Chemokines direct leukocyte migration Chemokine structure Small (7.5–12.5 kDa) proteins Possess highly conserved disulfide bonds that dictate both structure and category (six categories) Share two, four, or six conserved cysteine residues

Chemokine classes and their actions
Chemokine receptors are an example of G-protein-coupled receptors Seven-pass transmembrane receptors Transduce signals via interactions with a polymeric GTP/GDP-binding G protein Many receptors can bind to more than one chemokine; and several chemokines are able to bind to more than one receptor Chemokines direct leukocyte migration Signaling through chemokine receptors helps cells move to different body areas

Receptors and Cell Signaling
A cellular signal is any event that instructs a cell to change its metabolic or proliferative state Signals are usually generated by the binding of a ligand to a complementary cell-bound receptor A cell can become more or less susceptible to actions of a ligand by increasing or decreasing expression of the receptor for that ligand Cell signaling often induces a change in the transcriptional program of the target cell Sometimes multiple signals through multiple receptors are required to effect particular outcomes Integration of all signals received by a cell occurs at the molecular level inside the recipient cell

Antigen-mediated receptor clustering initiates signaling in B and T cells Receptor dimerization is often a result Multimerization can also occur Clustered receptors are localized in lipid rafts

Tyrosine phosphorylation is an early step in many signaling pathways CD3 (T cells) and Igα/β (B cells) are phosphorylated on ITAMs Immunoreceptor tyrosine activation motifs (ITAM) Phosphorylated tyrosines serve as docking points for adapter molecules

Tyrosine phosphorylation is an early step in many signaling pathways Src-family kinases phosphorylate tyrosines These kinases become activated themselves when phosphorylated

Adapter proteins help to gather members of signaling pathways Signal-inducing phosphatidyl bisphosphate (PIP2) breakdown by phospholipase C gamma (PLCγ) causes an increase in cytoplasmic calcium ion concentration Calcium ions can then bind several cellular proteins, changing their conformation and altering activity Calmodulin (CaM) is an important member of this group

The Ras/MAP kinase cascade activates transcription through AP-1 Ras is a G protein Activated when GTP exchanged for GDP Guanine-nucleotide Exchange Factors (GEFs) activate Ras by inducing this exchange GTPase activating proteins (GAPs) inhibit Ras by stimulating its ability to break down GTP into GDP Ras (once active) participates in downstream signaling events

The Ras/MAP kinase cascade activates transcription through AP-1 by these nuclear events Phosphorylated ERK (pERK) phosphorylates and activates Elk-1 transcription factor leading to production of the Fos protein Fos is phosphorylated by ERK and binds with phosphorylated Jun protein This pJun/pFos combination is known as transcription factor AP-1 AP-1 can facilitate transcription of the IL-2 gene

Phosphokinase C (PKC) activates Nuclear factor kappa B (NF-κB) NFκB inactive in the cytoplasm when bound to inhibitor (IκB) PKC phosphorylates IκB releasing it from NFκB Diacylglycerol activates PKC, activating IKK complexes IκB phosphorylation and ubiquitination targets it for destruction NF-κB translocates to the nucleus to enhance transcription

Immune responses and cell signaling
Antigen signaling includes Bringing dendritic cells into the required locations Macrophages and neutrophils upregulate phagolysosome activity and cytokine production Dendritic cells exhibit antigen peptides on MHC class I and MHC class II Cytoplasmic proteasomes process antigen to peptides Dendritic cells induced to secrete cytokine

Summary Signal transduction is a complex subject
The trick is to look for similarities and differences Both B and T lymphocytes use similar strategies once the processes are underway The differences lie at the level of the antigen receptors and the early membrane-linked events By understanding antigen receptor and early membrane event differences, we can better understand how signaling (and activation) works in each lymphocyte cell type

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