Molecular Interactions in Dendritic Cells and T Cells

Molecular Interactions in Dendritic Cells and T Cells

Lecture Overview

• Focus on molecular interactions between antigen presenting cells (APCs) and T cells.
• Emphasis on costimulatory and accessory molecules.

Lecture Outcomes

1. Reflect on the complexity of the immune cell surface and highlight the role of adhesion molecules.
      - Three mini outcomes within this focus:
        - Explore immune cell surface complexity.
        - Highlight the role of adhesion molecules in interactions.
        - Outline the two signal hypothesis of T cell activation.
2. Discriminate the roles of key costimulatory molecules.
      - Key molecules: CD28, CD80, CD86, CTLA-4.
3. Assess the immunological implications of the two signal system for T cell activation.
      - Explore why this system has evolved.
4. Introduction of additional costimulatory molecules.
      - Discuss ICOS and PD-1.
      - Summarize major molecular interactions in dendritic cell and T cell communication.

Outcome 1: Complexity of the Immune Cell Surface

• Importance of T cell receptor (TCR), MHC, and peptide interaction.
    - T cell recognition of antigen is not sufficient for T cell activation or proliferation.
• Visual representation of molecular interactions:
    - Complexity illustrated by densely packed proteins on T cells and dendritic cells (DCs).
    - High surface expression: T cells and APCs display hundreds of membrane proteins.
• Other surface proteins' functions:
    - Adhesion molecules: stabilize interactions between T cells and APCs.
    - Co stimulatory molecules: promote T cell activation.
    - Activating molecules: enhance APC activity.
    - Inhibitory/regulatory molecules: prevent excessive T cell activation.
• Adherence Mechanisms:
    - Initial adhesion via high-affinity interactions.
    - Allows T cell to sample numerous MHC molecules.
    - Critical: DCs express millions of MHC molecules with diverse peptide presentations.

Adhesion Molecules

• Examples of adhesion molecules:
    - CD2 and CD58
    - LFA-1 and ICAM-1
    - LFA-1 and ICAM-2
    - ICAM-3 and DC-SIGN
• Genetic Redundancy: If one adhesion molecule is knocked out, T cell and APC can still interact through others.
• Functionality:
    - Prolong interactions to ensure appropriate T cell sampling of antigen.
    - Dynamic nature: Degree of adhesion can change.
    - Integration of signaling pathways via TCR strengthens adhesion.
• Integral role of integrins:
    - LFA-1 is an integrin that transitions from low to high affinity upon TCR interaction with peptide-MHC complex, stabilizing cell interactions.
  

Co-stimulation and the Two Signal Hypothesis

• Two Signal Hypothesis
    - Proposed by Kevin Lafferty (1977).
    - Signal 1: T cell receptor recognition of peptide-MHC.
      - Alone, this signal is insufficient for activation; instead can lead to T cell anergy (inactivation).
    - Signal 2: Requires a second co-stimulatory signal (facilitated by APC) to activate the T cell.
• Defining Anergy:
    - Anergic T cell: Unable to respond to future antigenic challenges.
• Visual diagram description: Interaction of TCR and peptide-MHC displays the necessity of both signals for T cell activation.
• Importance of professional APCs
    - Professional APCs (like dendritic cells) provide both signals.
    - Nonprofessional APCs lack costimulatory signals => Leads to inactivation of T cells when only Signal 1 is received.
    - Mechanism crucial for immune regulation to avoid inappropriate activation of T cells.

Conclusion of Outcome 1

• Emphasis on revisiting co-stimulation and its intricacies in the next lecture outcome.
• The understanding of molecular interactions is vital for deciphering T cell activation and immunological responses.