Comprehensive Study Notes: PRRs, Innate Immunity, Dendritic Cell Migration, and Adaptive Lymphocyte Activation

Pathogen Recognition Receptors (PRRs) and Pathogen-Associated Molecular Patterns (PAMPs)

• Definition of PRRs (Pattern Recognition Receptors): Specialized host cell receptors localized on or inside cells that recognize specific molecular signatures associated with pathogens, particularly when a virus uncoats and exposes its nucleic acid genome.
• Viral PAMPs (Pathogen-Associated Molecular Patterns): The core PAMP associated with viral pathogens is viral nucleic acid (ribonucleic acid or viral genomic material).
• Subtypes and Spatial Localization of PRRs:
  • Toll-Like Receptors (TLRs): Located within host cellular membranes, specifically both the plasma membrane and the endosomal membrane.
    • Endosomal Localization Rationale: Many viruses enter host cells via endocytosis and uncoat within endosomes. Endosomal TLRs allow host cells to detect viral nucleic acid directly at this internal entry site.
  • RIG-Like Receptors (RLRs / RIG-I / RIG-1): Located in the cytoplasm of the host cell.
  • MDA5 (MDA-5 / NDO-5): Cytoplasmic receptors that detect viral nucleic acids when a virus uncoats directly in the cytoplasm.
  • Other Pathways: The cGAS-STING (sea GAS sting) pathway represents another cellular nucleic acid detection system.
• Spatial Surveillance Analogy (House Entry Metaphor):
  • Host cell surveillance operates like home security during a break-in: sensors must be placed at every potential entry point.
  • If a virus penetrates directly at the plasma membrane, its genome uncoats in the cytoplasm (monitored by cytosolic receptors like RIG-I or MDA5).
  • If a virus enters through endocytosis, its genome uncoats within the endosomal compartment (monitored by endosomal TLRs).
  • Having PRRs present in both the endosomal membrane and the cytoplasm ensures comprehensive detection regardless of the viral entry pathway.
• Interferon Response:
  • The primary and immediate functional consequence of PRR recognition of viral nucleic acid PAMPs is the robust production of interferon.
  • Paracrine Warning Mechanism: Interferon functions like a warning text message sent to neighboring cells, notifying them of a viral presence.
  • Antiviral State: Neighboring host cells respond to interferon by synthesizing antiviral proteins that inhibit viral replication upon potential infection.
  • Interferon release constitutes the immediate innate immune mechanism upon viral detection.

Cell Sorting: Innate vs. Adaptive Immune System

• Innate Immune System Components:
  • Macrophages
  • Natural Killer (NK) cells
  • Dendritic cells
• Adaptive Immune System Components:
  • B cells (at least $2$ B cells required for model demonstrations)
  • Helper T cells ($\text{CD4}^+$ T cells)
  • Cytotoxic T cells ($\text{CD8}^+$ T cells)
  • Plasma cells

Innate Immune Response at the Site of Infection

• Infected Host Cell Dynamics:
  • Upon viral infection and uncoating, small peptides derived from degraded viral proteins are displayed on the surface of the infected host cell via Major Histocompatibility Complex ($\text{MHC}$) receptors.
  • This presentation serves as a surface display signaling that the host cell is infected.
• Macrophage Activity:
  • Phagocytizes intact viral particles at the infection site.
  • Internalizes and degrades viral components to destroy the pathogen.
• Natural Killer (NK) Cell Activity:
  • Surveils host cells at the infection site.
  • Recognizes foreign viral peptides displayed on surface MHC receptors of infected host cells.
  • Induces apoptosis (programmed cell death) in the infected host cell to eliminate the viral replication niche.

Dendritic Cell Migration and Antigen Presentation

• Role at the Site of Infection:
  • Phagocytizes intact virus particles.
  • Degrades viral proteins into small viral peptide fragments internally.
  • Loads these degraded peptide fragments onto surface Major Histocompatibility Complex ($\text{MHC}$) molecules.
  • Mandatory Requirement: The dendritic cell must phagocytize and display viral peptides on its surface before leaving the infection site. Without displaying viral peptides, it cannot communicate with or activate T cells in the adaptive immune system.
• Migration to Lymphatics:
  • Leaves the infected peripheral tissue site.
  • Travels via afferent lymphatic vessels to the nearest lymph node, known as the draining lymph node.
  • Anatomical Rationale: The draining lymph node is the primary structural site where naive T cells and B cells reside and congregate.

Activation of the Adaptive Immune System in the Draining Lymph Node

• Cytotoxic T Cell Activation:
  • Receptor Specificity: Cytotoxic T cells interact with and recognize specific viral peptides displayed on MHC Class I ($\text{MHC I}$) on dendritic cells.
  • Clonal Expansion: Specific recognition of the peptide-$\text{MHC I}$ complex stimulates the individual Cytotoxic T cell to proliferate rapidly, creating an army of approximately $100$ identical cytotoxic T cell clones.
  • Effector Trafficking:
    1. Expanded Cytotoxic T cells exit the draining lymph node through efferent lymphatics.
    2. They enter the venous blood circulation.
    3. As blood circulates, Cytotoxic T cells extravasate out of the vasculature into the infected tissue site.
    4. They specifically identify and kill infected host cells displaying the matching viral peptide.

Helper T Cell Interaction and B Cell Activation

• Helper T Cell Activation:
  • Receptor Specificity: Helper T cells interact with and recognize specific viral peptides presented on MHC Class II ($\text{MHC II}$) on dendritic cells.
  • Clonal Expansion: Recognition triggers clonal expansion, producing an army of approximately $100$ identical Helper T cell clones.
  • T Cell Receptor Behavior: Helper T cells do not physically take or remove the peptide from the dendritic cell. The T Cell Receptor (TCR) binds the peptide-$\text{MHC II}$ complex to receive activation signals, after which the expanded T cells disassociate and move within the lymph node.
• Spatial Navigation in the Lymph Node:
  • The lymph node features distinct compartmentalized structures: a dedicated T cell region and a dedicated B cell region.
  • Activated Helper T cells travel from the T cell region to interact with B cells.
• B Cell Antigen Internalization and Presentation:
  • B Cell Receptors (BCRs): Surface BCRs (membrane-bound antibodies) on naive B cells specifically bind intact extracellular viral particles.
  • Processing: B cells phagocytize/endocytose the bound virus, degrade it into peptide fragments, and load these peptides onto surface MHC Class II ($\text{MHC II}$) molecules.
• Specific Helper T Cell - B Cell Cognate Interaction:
  • A Helper T cell will only interact productively with a B cell that displays the exact same viral peptide that the T cell originally recognized on the dendritic cell.
  • Example: If a Helper T cell specific for a brown viral peptide encounters a B cell displaying an orange peptide (from a different antigen), no productive interaction occurs; the T cell disassociates and continues searching.
  • When a Helper T cell encounters a B cell displaying the matching brown peptide on $\text{MHC II}$, the Helper T cell delivers essential activation signals to the B cell.
• B Cell Differentiation:
  • Cognate Helper T cell interaction induces the specific B cell to undergo clonal expansion.
  • The proliferating B cells differentiate into plasma cells, which actively secrete high titers of soluble antibodies specific for that viral antigen.

Cell Fate and Differentiation Dynamics

• Early Phase of Infection:
  • The primary differentiation pathway favors short-lived plasma cells to produce immediate, massive quantities of protective antibodies to clear the pathogen load.
• Late Phase of Infection:
  • As the infection resolves, lymphocyte differentiation shifts towards long-term immunity, producing:
    • Memory T cells
    • Memory B cells
    • Long-lived plasma cells

Class Logistics and Upcoming Schedule

• Friday Schedule:
  • First Case Study: Interactive group activity; no advance preparation required outside of attending class.
  • Practice Exam: Conducted during the same class session to assist with upcoming exam preparation.