T and B Cell Functions in Immune Responses

T and B Cell Functions in Humeral and Cell Mediated Immune Responses

• T and B cells have diverse functions in combating microbes, interacting with other cells and molecules in both the innate and adaptive immune systems.

Helper T Cells

• Helper T cells orchestrate the adaptive immune response.
• A dendritic cell presents peptide on MHC class II to activate a CD4 T cell, also receiving cytokine signals (signal three) to determine its subset.
• Helper T cells activate B cells for the humoral immune response and cytotoxic T cells for the cell-mediated immune response.

Subsets and Effector Functions

• Naive T cells differentiate into different effector T cells based on cytokine signals from dendritic cells, which are determined by the type of pathogen and pattern recognition receptor engaged.
  • Th1 cells: Activate macrophages to defend against intracellular vesicular pathogens.
  • Th2 cells: Act on eosinophils to defend against helminths.
  • Th17 cells: Act on neutrophils to combat extracellular pathogens like bacteria and fungi.
  • T Follicular Helper Cells: Activate B cells and drive antibody response against extracellular pathogens.
• Helper T cells secrete cytokines that act on innate and adaptive immune cells.

Th1 and Th17 Cells

• Th1 cells: Activate macrophages to kill intracellular microbes and activate cytotoxic T cells, which is important for viral infections and intracellular bacteria (especially if they escape into the cytosol).
• Th17 cells: Provide tailored responses for extracellular microbes.
  • Cytokines act on epithelial cells to produce antimicrobial peptides and tighten the barrier.
  • They also act on leukocytes to produce cytokines and recruit neutrophils to phagocytose bacteria and fungi.
• Th17 and Th1 cells activate inflammatory responses and phagocytes, involving macrophages and neutrophils.

Th2 Cells

• Th2 cells secrete cytokines important for macroscopic pathogens.
• They activate mast cells, basophils, and eosinophils, causing degranulation and release of toxic substances to kill worms.
• Th2 cell cytokines tell B cells to make IgE, which is important for mast cell and basophil degranulation.
• They also act on the intestine to increase mucus production and smooth muscle contraction for a "weep and sweep" response to expel pathogens.

Cytotoxic T Cells

• Cytotoxic T cells target intracellular pathogens, similar to natural killer cells, functioning against virally infected cells, cancer cells, and intracellular bacteria that escape the phagosome.
• A cytotoxic T cell, activated by a helper T cell, recognizes viral peptide on MHC on an infected cell and releases granules.
  • Perforin: Forms pores in the infected cell membrane.
  • Granzymes: Enter and induce apoptosis of the infected cell, eliminating the infection reservoir.
• Cytotoxic T cells are key to the cell-mediated immune response, also influencing the humoral immune response.

Humoral Immunity (B cells and Antibodies)

• Antibodies are secreted by plasma cells, which are differentiated B cells.
• There are five types of antibodies: IgM, IgD, IgG, IgE, and IgA, determined by the constant region (isotype).
• The B cell receptor is a membrane-bound antibody (IgM and IgD). Isotype switching is needed to produce IgG, IgE, and IgA.
• T follicular helper cells activate B cells for protein antigens, secreting cytokines that dictate the antibody isotype to produce.
  • Cytokine type depends on the pathogen that initiated the response.
  • This results in a switch from IgM to IgG, A, or E.
• Helper T cells also increase the quality (affinity) of the antibodies produced.

Antibody Locations and Functions

• IgM: Membrane-bound as a B cell receptor; secreted in pentamer form in the blood.
• IgD: Only acts as a B cell receptor.
• IgG: Found in the blood and extracellular fluid; transported to the placenta for fetal protection.
• IgA: Dimeric form in mucosal surfaces and breast milk; monomeric form in blood.
• IgE: Found under epithelial barriers, associated with mast cells for helminth protection.
• Antibodies have different functions depending on their isotype, allowing for tailored responses.

Antibody Structure and Function

• Antibodies are Y-shaped molecules with antigen-binding sites and a constant (Fc) region that determines the isotype.
• The Fc region mediates effector functions by binding to receptors on different cells.
• Antibodies bind to pathogens and link to innate immune cells or molecules to exert effector functions.

Effector Functions of Antibodies

• Neutralization: IgG and IgA block interactions between receptors and ligands, neutralizing pathogens or toxins.
• Opsonization: IgG enhances phagocytosis.
• Antibody-Dependent Cellular Cytotoxicity (ADCC): IgG mediates NK cell killing of infected cells.
• Sensitization and Degranulation: IgE sensitizes mast cells and basophils, leading to degranulation.
• Complement Activation: IgM and IgG induce complement activation.

Neutralization

• Antibodies bind and neutralize pathogens or toxins.
• They prevent intracellular pathogens from entering cells and neutralize toxins by blocking their binding to receptors.
• They prevent bacteria from colonizing host cells and viruses from infecting cells.

Phagocytosis

• Antibody (IgG) binds to bacteria, enhancing phagocytosis. IgM is also linked to phagocytosis.
• Complement is activated by antibody-bound bacteria, coating the surface for better phagocytosis.
• Macrophages and neutrophils recognize antibody and complement-coated bacteria better, leading to destruction.

Lysis

• Antibodies induce lysis in two ways:
  • Antibody-Dependent Cellular Cytotoxicity (ADCC): IgG binds to viral proteins on infected cells, activating NK cells to degranulate and induce apoptosis.
  • Complement-Mediated Lysis: IgG binds to antigens on bacteria, activating complement to form pores in the bacterial membrane and cause lysis.

Sensitization and Degranulation

• Sensitization occurs when an antibody binds to a receptor on a mast cell or basophil.
• IgE antibodies already bound to mast cells recognize antigens from macroscopic pathogens (worms), causing cross-linking, activation, and degranulation.
• Toxic substances are released to kill worms, linking IgE to helminth killing.

Adaptive Immune Response Summary

• Exposure to pathogen leads to dendritic cell activation of T cells (helper and cytotoxic T cells).
• Helper T cells orchestrate the immune response by activating B cells for the humoral response and cytotoxic T cells for the cell-mediated response.
• Memory cells are formed for future encounters with the same pathogen.
• If helper T cells are absent, the immune response is poor (e.g., in HIV infection).

Immune Effector Modules

• Innate and adaptive immune systems are highly integrated.
• Components can be categorized into immune effector modules for different pathogens.
  • Anatomical and chemical barriers, complement proteins, and innate cells comprise the innate immune system.
  • Inflammation, phagocytosis, degranulation, and cytotoxicity are mechanisms for eliminating microbes.
  • Dendritic cells link innate and adaptive immune systems by activating naive T cells.
  • T cells mediate cell-mediated immunity; helper T cells help other cells, and cytotoxic T cells kill infected cells.
  • B cells and antibodies are part of the humoral immune response.
  • Five antibody isotypes function in different ways to eliminate microbes.