Kuby Chapter 3: Sensations and Signaling

Sensations: Receptors and Signaling

• The presentation is about sensations, receptors, and signaling.
• Key concepts include receptor-ligand interactions, cytoplasmic signaling molecules, TNF functions, and transcription factors in T-cell activation.

Supporting Literature

• Kuby Chapters (Chapter 3) are referenced.
• Research on AP-1, NF-κB, NFAT pathways in innate lymphoid cells is discussed.
• CXC44 and HIV interaction is explored.
• Overview of TCR and TLR minireview is covered.

Discussion Questions

• 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 participating in antigen-dependent T-cell activation, and how do they work?

Session 2

• "Good communication is as stimulating as black coffee, and just as hard to sleep after." – Anne Morrow Lindbergh (quote)

Let's Bond...

• Receptor-ligand interactions involve non-covalent bonds.
  • Non-covalency: In immunology, cell-to-cell communication occurs via receptor-ligand interactions (non-covalent)
  • Affinity: Normally, the strength of the individual bonds is generally weak.
  • Avidity: Multiple bonds resulting in a high cumulative bind strength.
  • Valency: Increasing the valency of receptors increases avidity.

Immunoglobulin (BCR)

• Antibodies extend from the hinge region.
• Glycosylation helps spread heavy-chain domains apart, playing a functional role.
• Antibodies have an antigen-binding domain, binding two antigen molecules.
• Contains proline (flexible) and cysteine (heavy-chain dimer formation).
• Membrane-bound antibodies have extracellular, hydrophobic transmembrane, and cytoplasmic tails.
• Alternative splicing mechanisms produce secreted antibodies by removing/replacing these regions.

T-cell Receptor (TCR)

• Similar to BCR, contains immunoglobulin domains.
• TCR has α and β subunits, with constant and variable regions.
• Variable regions possess three CDRs forming peptide-specific binding sites.
• Constant regions contain transmembrane regions.
• Two types (αβ and γδ) with diverse antigen-binding characteristics.

Co-receptors

• Co-receptor binding enhances antigen-immune system receptor interactions.
• Interactions occur near the original receptor-ligand interaction.
• A single interaction may be insufficient for activation.
• Co-receptors can provide a second signaling interaction for complete cell activation.

Immunoglobulin 2-D and Space-Fill Models

• Two heavy chains (variable and constant regions) and two light chains held together by disulfide bonds.
• Models show variable and constant regions, hinge regions, antigen binding sites, and effector function sites.

Structural Differences

• Secreted antibodies are grouped into five major classes (IgA, IgD, IgE, IgG, IgM).
  • Each class differs in their heavy chain types (α, δ, ε, γ, μ).
  • Light chains are Kappa (κ) or Lambda (λ).
  • Different classes have different functions in immune responses.

Innate Immune Receptors

• Recognize PAMPs (Pathogen-Associated Molecular Patterns).
• Receptors for PAMPs, like Toll-like receptors (TLRs), are uniformly distributed on cell types.
• Receptors can be integral membrane proteins or intracellular proteins, recognizing recurring patterns on bacteria, yeast, and parasites.

Human PRRs

• TLR, CLR, RLR, NLR, and ALR are examples of human pattern recognition receptors (PRRs).
• Each PRR has a different cell location and recognizes different PAMPs.
• PRRs play essential roles in immune responses.

Signaling Molecules

• Cytokine signals are generated by ligand binding to cell receptors.
• Cytokine-receptor binding is noncovalent (typically high affinity).
• Cytokine-signaling results in changes in the target cell's transcriptional program, inducing metabolic or proliferative changes.

How Cytokines Work

• Cytokines are proteins that mediate immune responses.
• They act through three different mechanisms (endocrine, paracrine, and autocrine).

Cytokine Action

• Cytokine action can be pleiotropic (different biological effects), redundant (similar effects), synergistic (combined effects greater than additive), antagonistic (opposite effects), and cascade effect. (multiple downstream cytokines).

Practical Examples

• Presentation of many practical examples of cytokine actions on various immune cells.

The Six Cytokine Families

• Summarization of six major cytokine families (IL-1, Class 1/2, TNF, IL-17, Interferons, etc.).
• Each family has representative members with diverse functions and roles in immune responses.

Receptor Meets Ligand

• Ligand binding to a receptor causes conformational changes, dimerization/clustering, membrane location changes, and covalent modifications.

Adaptive Immune Receptors

• Summary of adaptive immune receptors (immunoglobulins – BCR, and TCR).
• Important receptors are highlighted (immunoglobulin domains, variable and constant regions, etc.).
• Additional related components like co-receptors (CD4, CD8), and tyrosine kinases with their specific roles are noted.

Putting It All Together

• Summary of the overall process and key features of immune responses and cell signaling. Summarizes the process.

NFAT and NFκB Detail

• Diagram illustrates the intricate interplay of NFAT and NFκB in response to antigen stimulation.

AP-1 Detail

• Diagram showing AP-1 activation pathway induced by extracellular stimuli leading to changes in gene transcription.

Comparison of B and T Cells

• Compares and contrasts B-cell and T-cell receptors, accessory proteins, ligands, co-receptors, tyrosine kinases, adaptor proteins, and effector molecules involved in their signaling pathways.

Lift Off...

• Summary of immune cell functions in response to infection: leukocytes, macrophages, neutrophils, dendritic cells, B cells, and T cells.

Session 3 Prepare

• Important questions regarding the innate immune system (innate components, role of phagocytes, and properties of neutrophils and macrophages).