Kuby Immunology: Detailed Notes on Cell-Mediated Cytotoxic Responses

Chapter 14: Cell-Mediated Cytotoxic Responses

Introduction

  • The sixth edition of Kuby Immunology provides insights into the mechanisms of cell-mediated cytotoxicity, detailing the roles of T cells and their interactions with antigen-presenting cells.

Section 1: Characteristics of T Cells

Comparison of Naive and Effector T Cells (Table 14-1)

  • Costimulatory Signal:

    • Naive T cells: Required activation through interaction between CD28 and B7.
    • Effector T cells: Not required for activation.

  • CD45 Isoform:

    • Naive T cells: CD45RA isoform.
    • Effector T cells: CD45RO isoform.

  • Cell Adhesion Molecules:

    • Naive T cells: Low expression of adhesion molecules (e.g., CD2, LFA-1).
    • Effector T cells: High expression of adhesion molecules.

  • Trafficking Patterns:

    • Naive T cells: Homing to high-endothelial venules (HEVs) in secondary lymphoid tissues.
    • Effector T cells: Migration to tertiary lymphoid tissues and inflammatory sites.

Section 2: Effector Molecules of T Cells (Table 14-2)

Types of Effectors Produced by Effector T Cells

  • Cytotoxic T Lymphocytes (CTLs):

    • Soluble Effectors:
    • Cytotoxins (perforins and granzymes), IFN-γ, TNF-β.
    • Membrane-Bound Effectors:
    • Fas ligand (FASL).

  • T Helper 1 (TH1) Cells:

    • Soluble Effectors:
    • IL-2, IL-3, TNF-β, IFN-γ, GM-CSF (high levels).

  • T Helper 2 (TH2) Cells:

    • Soluble Effectors:
    • IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, GM-CSF (low levels).
    • Membrane-Bound Effects:
    • CD40 ligand.

Section 3: Activation and Licensing of CTLs

CTL Activation
  • Activation Process:
    • Requires licensing of antigen-presenting dendritic cells for co-stimulatory signaling (Figure 14-1).
    • Signals provided by helper T cells (specifically TH1) enhance CTL activation:
    • Dendritic cells deliver a 'stronger' signal to naive CTL precursor cells (CTL-P).
Memory CTLs
  • Memory CTL precursors do not require helper T cells for activation; remain responsive due to past exposures (Figure 14-2).

Section 4: CTL Mechanisms of Action

Conjugate Formation
  • CTLs form conjugates with target cells to initiate cytotoxic action (Figure 14-6).
  • Mechanisms of granule exocytosis leading to target cell lysis include:
    1. Granule Conjugate Formation:
      • CTL binds to target cell, leading to localized cytoplasmic rearrangement.
    2. Exocytosis of Cytotoxic Granules:
      • Release of perforins and granzymes directed at the target cell (Figure 14-9).
Perforin and Granzymes

  • Perforin Pathway:

    • Perforins polymerize to form pores in the target cell membrane, facilitating protein entry (Figure 14-9a).

  • Granzyme Activation:

    • Granzymes enter via the perforin-created pores and activate apoptotic pathways:
    • Trigger caspase cascades and subsequent cellular apoptosis (Figure 14-11).
Pathways of Apoptosis

  1. Fas Pathway (Figure 14-11a):

    • Involves Fas ligand (FasL) binding to Fas receptor.
    • FADD complex activates downstream caspases leading to apoptosis.

  2. Perforin/Granzyme Pathway (Figure 14-11b):

    • Granzymes enter through perforin-formed pores, activate procaspases, leading to apoptosis.

Section 5: Innate Immunity: Role of NK Cells

Natural Killer (NK) Cells
  • Functions and activation through MHC Class I recognition (Figure 14-14).
  • NK cells differentiate between normal and infected cells based on MHC expression.
  • Inhibit killing signal when Class I MHC is present (Figure 14-14a) but initiate killing when absent or downregulated (Figure 14-14b).
Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
  • Mechanisms and involved cell types (NK cells, macrophages, etc.) that target cells marked by antibodies (Figure 14-15).

Section 6: Bridging of Innate and Adaptive Immunity

NKT Cells
  • NKT cells bridge both immune systems, characterized by:
    • Expression of T cell receptors (TCRs) responding to glycolipid antigens activated by CD1d molecules.
    • Function as both helper and cytotoxic cells without forming memory cells.

Conclusion

  • CTLs and NK cells play significant roles in the immune system's ability to combat infections and clear malignancies.
  • Understanding the pathways of activation, recognition, and cytotoxic mechanisms provides insight into therapeutic strategies for infectious diseases and cancer.