Immunology: Receptors and Signal Transduction

Sensations: Receptors and Signaling

• The presentation discusses receptors and signaling, focusing on the interaction between ligands and receptors.
• Supporting literature includes Kuby Chapters (Chapter 3) and research on AP-1, NF-κB, NFAT pathways in innate lymphoid cells.
• Other research areas mentioned are CXC44 and HIV, TCR/TLR, HIV-membrane fusion, and CXCR4/HIV.
• TCR/TLR overview and TLR minireview are also mentioned in the supporting literature.

Discussion Points

• Question 1: What are the cytoplasmic signaling molecules, and what do they do?
• Question 2: What are the principal functions of TNF?
• Question 3: What are the three main transcription factors involved in antigen-dependent T-cell activation, and how do they work?

Bonding in Immunology

• Cell-to-cell communication in immunology relies on receptor-ligand interactions.
• Non-covalency: In immunology, cell-to-cell communication occurs through receptor-ligand interactions via non-covalent forces.
• Affinity: The strength of individual bonds in these interactions is usually weak.
• Avidity: Multiple bonds increase the cumulative binding strength.
• Valency: Increasing receptor valency enhances avidity.

Univalent and Bivalent Interactions

• Univalent interaction: A simple "on-off" interaction.
• Bivalent interaction: The interaction is enhanced due to multiple binding sites.

Receptor Expression

• Receptor expression can change dynamically in response to external cues.
• Receptor expression varies over time during infections and other biological processes.

Receptor-Ligand Interactions

• When a ligand binds to a receptor, it causes:
  • Conformational change
  • Dimerization (and clustering)
  • Changes in membrane location
  • Covalent modifications

Benefits of Multimerization

• Cell-cell interactions are often maintained over long periods by high affinity binding.
• Extended contact enables signal transduction and cytokine exchange.

Adaptive Immune Receptors

• Immunoglobulins bear immunoglobulin domains
• The B-cell receptor (BCR) binds foreign antigens.
• The BCR is known as an antibody when secreted.
• The T-cell receptor (TCR) recognizes foreign or self-peptides presented on MHC molecules
• Associated molecules (CD4 and CD8) aid in defining T-cell subset functions

Co-receptors are Key

• Co-receptors enhance antigen-immune system receptor interactions by binding.
• Co-receptors usually work near the initial interaction site.
• Co-receptor interactions may provide secondary signaling for activation.

Immunoglobulin (BCR) Structure

• Antibodies have regions for antigen binding (Fab) and effector activity (Fc).
• Heavy and light chains form the antibody structure.
• Disulfide covalent bonds hold antibody chains together.
• Carbohydrate groups (CHO) are present on the antibody structure.
• Critical regions on antibodies include the hinge and the antibody's arms to antigen receptors.
• The binding region facilitates the spreading of heavy chain domains.

Structural Differences in Antibodies

• Antibodies are categorized into five major classes (isotypes/classes).
• IgA, IgD, IgE, IgG, and IgM, each is differentiated by their heavy chains (α, δ, ε, γ, and μ chains, respectively).
• Different classes of antibodies have specialized roles in the immune response.

T-cell Receptor (TCR)

• TCRs possess immunoglobulin domains, analogous to BCRs.
• TCRs comprise two subunits (α and β), each with variable and constant regions.
• Variable regions contain three complementarity-determining regions (CDRs), which interact with antigen-peptide complexes.
• Constant regions contain transmembrane and intracellular regions.
• Two types of TCRs (αβ and γδ) exist with various antigen-binding characteristics.
• Many aspects of TCR function depend on the relationship with CD4 and CD8.

Signal Transduction

• TCR signal transduction occurs via the CD3 complex.
• BCR signal transduction is mediated by Iga and Igß, including accessory molecules (CD19, CD21, and CD81).

Innate Immune Receptors

• Innate immune receptors recognize Pathogen Associated Molecular Patterns (PAMPs).
• Receptors for PAMPs may uniformly recognize numerous pathogens.
• Receptors for PAMPs are not clonally distributed but are found equally across cell types.
• PAMP receptors can be membrane-integrated or intracellular proteins.

Human PRRs

• Toll-like receptors (TLRs): recognize diverse microbial molecules, leading to inflammation and antimicrobials.
• C-type lectin receptors (CLRs): involved in phagocytosis and inflammation.
• Retinoic acid inducible gene (RIG)-like receptors (RLRs): recognize intracellular viral RNA.
• Nucleotide-oligomerization domain (NOD)-like receptors (NLRs): recognize bacteria.
• Absent-in-melanoma (AIM)-like receptors (ALRs): primarily recognize viral and bacterial DNA and proteins.

Cytokine Signaling Molecules

• Cytokine signals are initiated by ligand binding to a complementary receptor.
• Cytokine-receptor binding is primarily mediated through non-covalent forces.
• The consequences of cytokine receptor interaction are often significant changes in the target cell's transcription program, influencing various cellular processes (like metabolic or proliferative activity).
• Cytokines can trigger responses through endocrine, paracrine, or autocrine signaling mechanisms, affecting distant cells, nearby cells, or the cell producing the cytokine, respectively.

Cytokine Actions

• Pleiotropic: One cytokine can exert diverse effects depending on the target cell.
• Redundant: Multiple cytokines can perform similar functions.
• Synergy: Combining cytokines can produce effects greater than the sum of their individual effects.
• Antagonistic: One cytokine can inhibit the effect of another.
• Cascade: A cytokine can trigger a series of events, producing additional cytokines.

Examples of Cytokine Families

• Interleukin-1 (IL-1) family, including IL-1α, IL-1β, and IL-1Ra
• Class 1 cytokine family: Includes proteins like IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-12.
• Class 2 cytokine family: Primarily characterized by Interferons (IFNs)
• Tumor necrosis factor (TNF) family: TNF-α and TNF-β
• Interleukin-17 (IL-17) family
• Chemokines

Chemokines

• Chemokines are small proteins (7.5–12.5 kDa).
• Chemokines possess highly conserved disulfide bonds.
• Chemokines share conserved cysteine residues, categorizing them into subclasses (e.g., CXC, CC, CX3C).

Chemokine Receptors

• Chemokine receptors are G-protein-coupled receptors (GPCRs).
• They transmit signals utilizing G proteins (GTP/GDP cycle).
• Many receptors bind various chemokines.
• Multiple chemokines can bind to one receptor.

Cell Signaling

• A cellular signal is any event instructing a cell to adjust metabolic or proliferative status.
• Signals are generated through ligand binding to a complementary receptor.
• Cells alter their susceptibility to ligands by upregulating or downregulating receptor expression.

Putting It All Together

• The presentation ends with a summary emphasizing the fundamental processes involved in immune responses and cell signaling.

NFAT and NF-κB Detail

• The presentation describes the roles of NFAT and NF-κB in immune responses, and how signaling molecules influence their activity.
• NFAT and NF-κB are critical signaling pathways involved in gene expression regulation influencing cell-to-cell signaling, and influencing cell activation and differentiation responses.

Antigen Presenting Cell (APC) and Cell Signaling

• APCs carry out actions relevant to antigen presentation and cell signaling.
• These processes include getting dendritic cells to required locations, upregulating phagocytic activity in macrophages and neutrophils, and cytokine production, and importantly presenting antigen peptides through MHC-I and MHC-II in dendritic cells.

General Immune Response Processes

• The presentation describes the processes involved in general immune responses including leukocyte migration, phagocyte activation, and dendritic cell function in antigen presentation.
• In general, these involve processes in the cells, including activation of immune responses and cytokine production.
• The presentation details the effects of these cell-level processes on the systemic body-wide immune response.

AP-1 Detail

• The presentation outlines the MAPK pathways and transcription factors, including AP-1, crucial in various cellular processes.
• Describes the role of AP-1 factors (fos and jun) in cellular proliferation, differentiation, and apoptosis.
• Discusses the association between AP-1 and diverse biological processes (such as cellular transformations, inflammation, and immune disorders).

B-cell and T-cell Components

• Key components involved in B-cell function (receptor structure, accessory proteins, relevant ligands, co-receptors, and key effector molecules) are described.
• An overview of T-cell receptor components, accessory proteins, ligands, co-receptors, and effector molecules is similarly detailed.

Test your knowledge on the critical roles of receptors and ligands in immunology. This quiz covers various aspects including T-cell receptors, cytokines, and the mechanisms of signal transduction. Explore the dynamics of receptor-ligand interactions and their impact on immune responses.