BIO 4750 Immunology Chapters 1-4

Course Information

• Course title: BIO 4750 Basic and Clinical Immunology
• Course instructor: Dr. Desiree Seib
• Course date: Friday, January 17, 2025
• Reading material: Chapters 1-4

Learning Objectives

• Overview of the adaptive immune system
• Mechanisms of pathogen recognition by adaptive immune cells
• Timeline of an adaptive immune response

Primary Lymphoid Tissue

• Sites where lymphocytes develop and mature
• Bone marrow:
  • Produces B cells and T cells
  • B cells mature
• Thymus:
  • T cells develop and mature

Secondary Lymphoid Tissue

• Sites where antigens from pathogens trigger adaptive immune responses
• Lymph nodes:
  • Important in lymphocyte activation
  • Connect circulatory and lymphatic systems
  • Part of lymphatic system of vessels that drain extracellular fluid lymph from tissues to blood
• Spleen:
  • Macrophages and dendritic cells are important for clearing bloodborne pathogens
  • Activates T cells and B cells circulating through the blood
  • Individuals without a spleen are more prone to bloodborne bacterial infections
  • Antigen presentation and lymphocyte activation occurs in the white pulp
• Mucosa-associated lymphoid tissue (MALT):
  • Found in mucous membranes (digestive, respiratory, and urogenital)
  • Structurally similar to lymph nodes and spleen
  • Gut-associated lymphoid tissue (GALT) and bronchial-associated lymphoid tissue (BALT)
  • Gains antigens for presentation to lymphocytes through M cells in the gut

Study Questions

• Which cells have antigen receptors that are highly specific and can distinguish between different strains of bacteria or viruses?
• Which molecules have a variable region and one or more constant regions?
• Which membrane protein can bind to an αβ T-cell receptor?
• In which lymphoid organ does activation of naïve B and T cells take place?
• Which immune cells would be absent in a mouse that has no thymus?

T-Cell Receptors

• Transmembrane proteins with very short cytoplasmic tails
• Heterodimers of an α-chain and a β-chain (most common) or a γ-chain and a δ-chain
• Each chain has an N-terminal variable region and a constant region closer to the membrane
• Variable regions of the two chains form the antigen-binding site

Antigen Recognition by T-Cell Receptors

• Each T cell has a unique T-cell receptor
• T-cell receptors bind only short peptides
• Peptides must be presented by an MHC molecule
• Each T cell responds to a specific peptide presented by the specific MHC molecule

MHC Molecules

• Bind peptides, T-cell receptors, and a co-receptor
• Class I MHC:
  • Presents peptides from cytosolic proteins
  • Binds to CD8 coreceptor on CD8+ T cells
• Class II MHC:
  • Presents peptides from externally acquired proteins
  • Binds to CD4 coreceptor on CD4+ T cells

Immunoglobulins

• Also known as antibodies
• Serve as B-cell receptors when expressed as a cell surface protein with a transmembrane domain
• Serve as soluble effector molecules when secreted by activated and differentiated B cells called plasma cells
• Basic structure: 4 polypeptide chains (2 identical heavy chains and 2 identical light chains) held together by disulfide linkages
• Heavy and light chains have variable and constant regions
• Variable regions form a single antigen-binding site
• Each immunoglobulin has 2 identical antigen-binding sites

Secreted Soluble Immunoglobulins

• 5 different isotypes
• Effector functions:
  • Neutralization of foreign particles or pathogens
  • Opsonization
  • Complement activation
  • Activation of innate immune cells
  • Protection of internal mucosal surfaces

Comparing Innate and Adaptive Immunity

• Innate and adaptive immune systems functionally overlap and complement each other
• Innate immune cells have receptors for constant regions of immunoglobulins
• Immunoglobulins can activate the classical pathway of complement activation
• Dendritic cells present peptide antigens to T cells
• Innate immune system clears common pathogens; adaptive immunity targets novel pathogens

Adaptive Immune System Differences

• Adaptive immunity has a memory function that innate immunity lacks.
• Adaptive immunity involves highly specific receptors that can distinguish between different pathogens.

T and B Cell Development

• T cells mature in the thymus
• B cells develop in the bone marrow
• Both undergo somatic recombination of their receptor genes followed by selection to ensure receptors that won't recognize self-antigens

Antigen Processing and Presentation

• Dendritic cells phagocytose pathogens at the site of infection and migrate to lymph nodes
• Cytosolic pathogen proteins are processed in the cytosol presented on class I MHC molecules
• Extracellular pathogen proteins are processed in phagolysosomes, presented on class II MHC molecules

T Cell Clonal Selection/Expansion

• Dendritic cells present peptides to circulating T cells that interact via cell-adhesion molecules
• T-cell receptor and co-receptor engagement with MHC + peptide results in signaling and activation
• Activation results in T-cell division and differentiation
• CD8 T cells differentiate into cytotoxic T cells
• CD4 T cells differentiate into helper T cells

B Cell Clonal Selection/Expansion

• Some helper T cells migrate to parts of lymph nodes where they encounter circulating B cells.
• B cells that recognize the same pathogen as the T cell become activated, divide, and differentiate.

B Cell Differentiation

• Depending on cytokine signals from helper T cells, some B cells differentiate into antibody-secreting plasma cells.
• Some progeny B cells become memory B cells
• Other B cells undergo further refinements to their B-cell receptor:
  • Somatic hypermutation and selection generate higher affinity.
  • Recombination of heavy chain constant region genes result in a different heavy chain type (isotype switching)

Mechanisms of Diversity in T-cell and B-cell Receptors

• Genetic mechanisms for receptor diversity
• Recombination of different variable gene segments
• Addition or removal of random nucleotides at junctions of variable gene segments