Immune Cell Signaling: Receptors, Ligands, and Pathways

What unique challenges do immune cells face compared to other cells?

Pathogen recognition and long-distance communication.

How do immune cells detect and respond to signals?

They rely on receptors to detect molecular signals and translate them into cellular responses such as growth, division, differentiation, migration, and altered metabolism.

What are the three main types of immune receptors?

Pattern Recognition Receptors (PRRs), Adaptive Immune Receptors (BCRs and TCRs), and Cytokine/Chemokine Receptors.

What are Pattern Recognition Receptors (PRRs) and where are they found?

PRRs are found on innate immune cells (macrophages, dendritic cells, neutrophils) and some adaptive immune cells (B and T cells) and recognize conserved molecular patterns on pathogens.

What are B-cell receptors (BCRs) and T-cell receptors (TCRs)?

BCRs are antigen-specific receptors on B lymphocytes, while TCRs are antigen-specific receptors on T lymphocytes.

What is the role of cytokine and chemokine receptors in the immune system?

They allow communication between immune cells and direct cell migration to tissues or lymphoid organs.

What types of interactions do immune receptors use to bind ligands?

Noncovalent interactions such as hydrogen bonds, ionic bonds, hydrophobic interactions, and Van der Waals forces.

What is the significance of receptor-ligand binding stability?

It must be stable enough to trigger a signal but reversible to allow dynamic immune responses.

What intracellular actions can receptor-ligand binding trigger?

Activation or suppression of gene expression, cellular proliferation, cytokine or chemokine secretion, and differentiation into effector or memory cells.

What does the dissociation constant (Kd) indicate in receptor-ligand interactions?

Kd quantifies the strength of binding between a receptor and its ligand; a lower Kd indicates stronger binding (higher affinity).

How is receptor occupancy determined at a given ligand concentration?

When 50% of receptors are occupied, the concentration of receptor-ligand complexes equals the concentration of free receptors.

What are typical affinity ranges for early antigen-antibody interactions?

Approximately 10−6 to 10−8 M.

What is the affinity range for high-affinity antibodies in the late immune response?

Approximately 10−10 M.

What do innate Toll-like receptors recognize?

Pathogen-associated molecular patterns.

What measurement method can be used to assess receptor-ligand interactions?

Equilibrium dialysis measures free versus bound ligand at equilibrium.

What is the role of immune cells in integrating signals from multiple receptors?

They must integrate signals to determine the overall cellular response.

What is the significance of high-affinity binding in immune receptor interactions?

It requires many weak bonds acting together and precise molecular complementarity.

How do immune receptor-ligand interactions differ from enzyme-substrate interactions?

They can be multivalent, exhibit extremely high affinity, and involve a diverse repertoire of receptors.

What is the function of chemokines in the immune response?

Chemokines direct cell migration to tissues or lymphoid organs.

What is the biological significance of receptor-ligand binding in immune signaling?

It triggers signal transduction, converting extracellular signals into intracellular actions essential for immune responses.

What is the relationship between receptor-ligand affinity and Kd?

The lower the Kd, the stronger the binding and higher the affinity between receptor and ligand.

What is the role of immune cells in tissue trafficking?

Proper receptor signaling is critical for immune activation, differentiation, and tissue trafficking.

What is the importance of receptor signaling in immune cell function?

It is crucial for activation, differentiation, and the ability to respond to pathogens.

What types of immune cells rely on PRRs for pathogen detection?

Macrophages, dendritic cells, and neutrophils primarily rely on PRRs.

What does K_d represent in receptor-ligand binding?

K_d (dissociation constant) provides a quantitative measure of receptor-ligand binding strength, with lower K_d indicating higher affinity.

What is the significance of K_d when [L] equals K_d?

At [L]=K_d, 50% of receptors are occupied.

Define a monovalent receptor.

A monovalent receptor has a single ligand-binding site.

Define a multivalent receptor.

A multivalent receptor has two or more ligand-binding sites per receptor molecule.

What is a bivalent B-cell receptor (BCR)?

A bivalent B-cell receptor binds to two identical antigens on a bacterial surface.

How do multivalent interactions affect binding strength?

Multivalent interactions strengthen overall binding beyond the sum of individual monovalent interactions.

What is the role of geometric strain in multivalent binding?

Slight geometric strain may reduce the binding efficiency of each individual site, but overall binding remains stronger than a single site.

What is the difference between avidity and affinity?

Affinity is the strength of binding between one receptor site and one ligand site, while avidity is the overall strength of binding when multiple receptor-ligand interactions occur simultaneously.

Why is avidity always higher than individual affinities?

Avidity is higher because multiple weak interactions collectively produce a strong and stable association.

What conditions allow monovalent receptors to function in a multivalent manner?

Monovalent receptors can function in a multivalent fashion if the ligand is multivalent and receptors can diffuse in the fluid cell membrane.

How does receptor clustering enhance signal transduction?

Sequential binding of ligand to multiple receptors leads to cluster formation, stabilizing the ligand-receptor interaction and enhancing signal transduction.

What is the challenge faced by immune receptors?

Immune receptors must recognize a vast diversity of antigens and signaling molecules despite a limited number of receptor-coding genes.

How does the immune system expand receptor diversity?

The immune system uses combinatorial strategies, such as pairing protein chains, to create multiple unique binding sites from a limited set of genes.

What is the structure of Class 1 cytokine receptors?

Class 1 cytokine receptors consist of three different alpha (α) chains that can pair with the same beta (β) chain.

How do B-cell receptors (BCR) achieve antigen specificity?

BCRs are composed of a heavy (H) chain and a light (L) chain, both contributing to antigen specificity.

What is the structure of T-cell receptors (TCR)?

TCRs have a two-chain structure, with diversity arising from different pairings of α and β chains.

What is the function of Toll-like receptors (TLRs)?

TLRs can form dimers (two monomers), increasing the range of ligands they can bind.

What is the key principle behind combinatorial pairing of protein chains in immune receptors?

Combinatorial pairing allows one chain to be reused in multiple receptor contexts, significantly increasing ligand-binding diversity.

Compare the number of receptors in innate vs. adaptive immune systems.

Innate receptors number around 100, while adaptive receptors (BCR & TCR) number in the billions.

How is diversity generated in innate vs. adaptive receptors?

Innate receptors are germline encoded and fixed, while adaptive receptors generate diversity through DNA recombination in individual lymphocytes.

What is the recognition capability of innate receptors compared to adaptive receptors?

Innate receptors have limited, hardwired recognition, while adaptive receptors can recognize virtually any antigen.

What is the process by which adaptive receptor genes are formed in B and T cells?

Adaptive receptor genes are encoded in fragments in germline DNA and are stitched together randomly in each individual B or T cell.

What analogy is used to describe the random recombination of receptor genes?

Building a meal by choosing one item from each section of a menu and linking them together.

What segments comprise the heavy chain gene in B cells?

The heavy chain gene consists of multiple segments: V, D, and J, which are randomly recombined.

What segments comprise the light chain gene in B cells?

The light chain gene consists of V and J segments, which are also randomly recombined.

What is the significance of pairing heavy and light chains in B cell receptors?

The pairing of heavy and light chains adds an extra layer of diversity to the receptor.

What are the components of T cell receptors (TCRs)?

TCRs consist of α and β chains that are encoded in gene fragments and recombined differently in each T cell.

What is junctional diversity in the context of receptor gene recombination?

Junctional diversity refers to small insertions or deletions at gene segment junctions during recombination, creating further variability.

What are the three key principles that contribute to receptor diversity in the adaptive immune system?

1. Combinatorial diversity - different gene segments recombined. 2. Pairing diversity - different heavy/light or α/β chain combinations. 3. Junctional diversity - random nucleotide changes at segment junctions.

How does adaptive receptor diversity compare to innate receptors?

Adaptive receptor diversity is extraordinarily large, with billions of unique receptors compared to about 100 innate receptors.

What happens to immune receptor expression when lymphocytes are activated?

Many immune receptors are dynamic; their cell surface expression changes depending on whether the cell is resting or activated.

What is the composition of the IL-2 receptor in resting versus activated lymphocytes?

Resting lymphocytes express IL-2Rβγ (two chains), while activated lymphocytes express IL-2Rαβγ (three chains).

What is the functional consequence of IL-2 receptor changes upon lymphocyte activation?

Activated lymphocytes can respond to IL-2, enabling proliferation and differentiation, while resting lymphocytes cannot.

What triggers the expression of IL-2Rα in lymphocytes?

The binding of lymphocytes to antigen through BCR or TCR induces the expression of IL-2Rα.

How do B-cell receptors change upon activation?

Resting B cells express both IgM and IgD; upon activation, IgD expression decreases while IgM remains.

How do receptor expression patterns affect immune responses?

Receptor expression patterns are dynamic, allowing precise regulation of immune responses based on activation.

What factors influence receptor-ligand interactions in the immune system?

Receptor-ligand interactions are influenced by affinity, avidity, and the anatomical context of the cells during the interaction.

What is the duration of T cell binding to dendritic cells during immune responses?

Helper T cells can remain bound to dendritic cells for 12 hours or more.

What occurs at the interface between T cells and dendritic cells during cytokine delivery?

The binding induces reorganization of the dendritic cell's microtubule-organizing center, directing cytokine-containing vesicles to the interface.

What is the outcome of mutual activation between T cells and dendritic cells?

Both dendritic and T cells can activate each other through directed cytokine release.

What happens during sequential interactions of activated T cells with other immune cells?

Activated T cells can move on to B cells or cytotoxic T cells, repeating the process of directed cytokine release.

What is the significance of local cytokine concentration at the cell interface during immune responses?

Local cytokine concentration is extremely high at the interface, ensuring efficient and accurate signal delivery, enhancing activation and coordination of the immune response.

What are cell-cell interactions in the immune system responsible for?

They allow directional, focused release of ligands, creating locally high concentrations that increase the strength and precision of immune signaling.

What is the core structure of an immunoglobulin (Ig) domain?

It consists of two β sheets forming a stable hydrophobic 'sandwich', with each sheet containing 3-6 β strands of alternating hydrophobic and hydrophilic residues, stabilized by intrachain disulfide bonds.

What are complementarity-determining regions (CDRs) and their role in B-cell receptors (BCRs)?

CDRs are flexible loops at the ends of β sheets in BCRs that are responsible for antigen binding.

What proteins are included in the immunoglobulin superfamily?

The immunoglobulin superfamily includes B-cell receptors (BCRs), T-cell receptors (TCRs), adhesion molecules, and other immune receptors.

How many Ig domains do antibody heavy and light chains typically have?

Antibody heavy chains have 4-5 Ig domains, while light chains have 2 Ig domains.

What is the significance of the N-terminal domain in antibodies?

The antigen-binding site is located in the N-terminal domain of the antibody.

What is the structural motif of the immunoglobulin fold?

The immunoglobulin fold provides a stable β-sheet framework with flexible loops that define ligand-binding specificity.

How does the B-cell receptor (BCR) exist in B cells?

The BCR exists in a membrane-bound form on naïve B cells, anchored via hydrophobic residues at the C-terminus of the heavy chain.

What is the difference between membrane-bound BCRs and secreted antibodies?

Membrane-bound BCRs have a hydrophobic C-terminus and serve as receptors, while secreted antibodies have a hydrophilic C-terminus and are produced after B-cell activation to bind antigens in extracellular fluids.

What types of receptors can be found in the innate immune system?

Innate immune receptors can be membrane-bound, soluble, or located inside cells, such as in endosomal or lysosomal membranes.

What is the relationship between BCRs and antibodies?

BCRs are membrane-bound immunoglobulins on B cells, while antibodies are the secreted form produced after B-cell activation, sharing the same antigen-binding site.

What is the structure of antibodies in terms of polypeptide chains?

Antibodies consist of 2 identical heavy (H) chains and 2 identical light (L) chains, with disulfide bonds linking the chains.

What defines the antigen-binding sites of antibodies?

The antigen-binding sites are formed from the variable regions of the heavy (V_H) and light (V_L) chains, with CDRs in these regions directly contacting the antigen.

What is the 3D structure of antibodies?

Antibodies have a Y-shaped structure with two antigen-binding sites at the tips of the arms.

What maintains the solubility and flexibility of antibodies?

Glycosylation maintains the solubility and flexibility of antibodies.

What is the role of intracellular receptors in the innate immune system?

Intracellular receptors detect intracellular pathogens or stress signals and can be located in endosomal or lysosomal membranes.

What is the importance of the loops in immunoglobulin domains?

Loops allow for flexibility and can adopt multiple conformations, which is crucial for the function of immune receptors.

What is the evolutionary significance of the immunoglobulin superfamily?

Members of the immunoglobulin superfamily are evolutionarily related and derived from a common primordial Ig-domain gene.

How do innate immune receptors differ in their location?

Innate immune receptors can exist in all four compartments: membrane-bound, secreted, associated with intracellular membranes, or cytosolic.

What is the function of the antigen-binding site in antibodies?

The antigen-binding site allows antibodies to specifically bind to antigens, facilitating immune responses.

What is the role of disulfide bonds in antibody structure?

Disulfide bonds stabilize the structure by linking the heavy and light chains together.

What is the significance of the C-terminus in the context of BCRs and antibodies?

The C-terminus determines whether the receptor is membrane-bound (hydrophobic) or secreted (hydrophilic).

What defines the different classes of antibodies?

Antibody classes are defined by their heavy chain constant regions: IgM (μ chain), IgD (δ chain), IgG (γ chain), IgA (α chain), and IgE (ε chain).

What are the light chain types in antibodies?

The light chains in antibodies are κ and λ, with λ having four subtypes, the most common being λ1.

What is the primary function of different antibody classes?

Different antibody classes mediate distinct effector functions such as phagocytosis and complement activation.

What is the expression of antibodies in immature and mature B cells?

Immature B cells express only membrane IgM, while mature B cells express both IgM and IgD.

What happens to IgD and IgM upon antigen stimulation in B cells?

Upon antigen stimulation, IgD is lost while IgM is maintained.

What is required for the expression of other antibody classes (IgG, IgA, IgE)?

The expression of IgG, IgA, and IgE requires DNA recombination and cytokine signals.

What role does CD21 play in B cell receptor (BCR) signaling?

CD21 binds complement-coated antigens (e.g., C3d) and increases the avidity of antigen recognition.

What is the function of CD19 and CD81 in BCR signaling?

CD19 and CD81 are involved in signal transduction but do not directly bind antigens.

Describe the structure and function of Igα and Igβ in BCR signaling.

Igα and Igβ are transmembrane heterodimers associated with BCR that contain ITAMs, which are phosphorylated upon antigen binding and serve as docking sites for downstream signaling molecules.

What is the process that occurs when an antigen binds to a BCR?

When an antigen binds to a BCR, it causes a conformational change, transmitting a signal via Igα/Igβ to downstream pathways.

What are the main functions of B cells and antibodies?

B cells and antibodies target soluble or extracellular antigens such as toxins, viruses, and bacteria.

What do T cells monitor in the body?

T cells monitor host cells for viral infections, malignant transformations, and the uptake of foreign proteins.