Cell-Mediated Immunity Study Notes

lecture details

  • Date: 13th November 2025
  • Lecturer: Dr. David Courtney
  • Topic: Cell-mediated Immunity
  • Course Code: IMM11
  • Course Reference: ESTP1845
  • Institution: Queen's University Belfast
  • Affiliation: Wellcome-Wolfson Institute for Experimental Medicine

Learning Outcomes

By the end of this lecture, students should be able to:

  • Explain phases of cell-mediated immune responses
  • List the cells, receptors, and steps involved in antigen presentation
  • Explain T cell subsets, receptors (TCR), activation, and T cell memory
  • Explain mechanisms of cell-mediated immunity and regulation

Overview of Cell-Mediated Immunity

  • Definition:
    • Cell-mediated immunity is the immune response that specifically targets intracellular pathogens, which include viruses, certain bacteria, and protozoa.
  • Distinctive Feature:
    • This immune response primarily involves T lymphocytes, in contrast to humoral immunity which primarily employs antibodies.
  • Contrast with Humoral Immunity:
    • Humoral immunity: Involves antibodies that neutralize extracellular pathogens.
    • Cell-mediated immunity: Works actively to kill infected host cells.

Phases of Immune Responses

  • The immune response to pathogens can be conceptualized in three critical phases, often referred to as the 3 R's:
    1. Recognition: Identifying the pathogen.
    2. Reaction: Mounting a response against the pathogen to eliminate it.
    3. Resolution: Concluding the immune response.

Immune Response To A Virus

  • Role of Innate and Acquired Immunity:
    • Both innate and acquired immunity are integrated during the immune response to a virus.
    • Key Components of Innate Immunity:
    • Natural Killer (NK) cells
    • Macrophages
    • Complement system
    • Cytokines
    • Key Component of Acquired Immunity:
    • antibodies (produced by B cells)
    • T cells (adaptive response)
  • Pathogen Response Timeline:
    • 0-4 hours: Activation of NK cells and release of interferons (IFN α and β) and IL-12.
    • 4-96 hours: Activation of cytotoxic T cells (CTLs), particularly upon the detection of heightened danger from the viral infection.

Antigen Presentation

  • Key Cells Involved:
    • Professional Antigen Presenting Cells (APCs):
    • Dendritic cells
    • Macrophages
    • B cells
  • MHC Molecules:
    • Major Histocompatibility Complex (MHC) molecules function in antigen presentation.
    • Class I MHC: Handles presentation for CD8+ T cells.
    • Class II MHC: Handles presentation for CD4+ T cells.

Antigen Recognition By T Cells

  • MHC Class I Molecules:
    • Are expressed on all nucleated cells.
    • CD8+ cytotoxic T cells recognize antigens presented on MHC Class I.
  • MHC Class II Molecules:
    • Are expressed only on professional antigen-presenting cells (APCs: Dendritic Cells, B cells, Macrophages).
    • CD4+ Helper T cells recognize antigens displayed on MHC Class II molecules.

Steps in Antigen Presentation

  1. Uptake and processing of the pathogen by the APC.
  2. Loading of peptide fragments onto MHC molecules.
  3. Migration of the APC to lymphoid tissues (e.g., lymph nodes).
  4. Presentation of the processed antigen to naïve T cells, requiring additional co-stimulatory signals (CD80/CD86 ↔ CD28).

T Cell Subsets and their Functions

  • CD4+ (Helper) T Cells:
    • Monitor leukocytes for the presence of antigen fragments in their class II MHC molecules and react accordingly.
  • CD8+ (Cytotoxic) T Cells:
    • Monitor all body cells for foreign antigen fragments in their class I MHC molecules.
    • Require assistance from CD4+ T cells for effective activation and response.

T Cell Antigen Receptor (TCR)

  • Structure:
    • Composed of variable (V) and constant (C) domains organized in an immunoglobulin gene superfamily.
    • Resembles the Fab fragment of an antibody, with a binding site and a cytoplasmic tail for transducing signals.
  • Diversity:
    • High diversity in TCR sequences, estimated at around 2imes1072 imes 10^7 different TCRs in humans.
    • Each clone of TCRs responds to a specific antigen.

Cytotoxic T Lymphocyte (CTL) Recognition

  • Mechanism:
    • CTL recognition involves the interaction between MHC Class I molecules and the T Cell Receptor (TCR).
    • Allows virus-infected cells to present viral antigens, which are recognized and targeted for destruction by CD8+ cytotoxic T cells.

CTL Effector Functions

  • Mechanism of Action:
  1. CTLs bind to virus-infected cells.
  2. Release of cytotoxic proteolytic enzymes, including perforin and granzymes.
    • Perforin: Creates pores in the target cell membrane.
    • Granzymes: Enter through the pores to induce apoptosis by breaking down the target cell's DNA and activating its cytoskeleton.
  3. Infected cells begin to fragment and are cleared away by phagocytic cells (resolution phase).

Cytotoxic Activity of CTLs

  • Products of Cytotoxicity:
    • Perforins: Polymerize to create channels in target cell membranes leading to leakage.
    • Granzymes: Degrade target cell DNA into oligomers.
    • TNF-β: Inhibits protein synthesis in the target cell, contributing to cell death.
    • Serine Proteases: Degrade membrane proteins of the target cell.
    • Nucleases: Degrade both DNA and RNA.
    • Fas Ligand: Binds to Fas receptors on target cells to induce apoptosis.

Natural Killer (NK) Cells

  • Characteristics:
    • NK cells are innate immune cells that identify and destroy certain infected and tumor cells without requiring prior sensitization.
  • Mechanism:
    • Recognize cells that lack MHC Class I molecules, which normally inhibit NK cell activity.
    • Utilize perforins and granzymes to induce apoptosis in target cells (reaction phase).

Innate/Adaptive Responses (ADCC)

  • Mechanism of Antibody-Dependent Cellular Cytotoxicity (ADCC):
    • Antibodies bind to virus-infected cells, marking them for destruction.
    • NK cells bind to these antibodies through CD16 receptors, leading to the release of cytotoxic granules and antiviral cytokines to kill the infected cells.
    • Resulting in apoptosis of infected cells.

Innate/Adaptive Interactions

  • Innate Immunity: NK cells will attack virally infected cells that downregulate MHC Class I.
  • Innate/Adaptive Functions: NK cells can assist in ADCC.
  • Adaptive Immunity: Functions of cytotoxic T cells primarily serve to recognize and kill infected target cells.

Regulation of Cell-Mediated Immunity

  • Regulatory T Cells (Tregs):
    • Release immunosuppressive cytokines like IL-10 and TGF-β to inhibit immune responses.
  • Checkpoint Molecules:
    • CTLA-4 and PD-1 are molecules that inhibit T cell activation to maintain immune homeostasis.
  • Cytokine Balance:
    • Critical in preventing excessive inflammation and ensuring a regulated immune response.

Memory in Cell-Mediated Immunity

  • IL-2 involvement:
    • Pathogen recognition in T cells leads to potential outcomes: proliferation, apoptosis, or memory formation.
    • Memory T cells maintain specificity towards antigens for long-term protection and response readiness.

Clinical Relevance

  • Example:
    • The HIV-1 Nef protein down-regulates MHC expression on infected cells and redistributes co-stimulatory molecules CD80 and CD86 away from the surface of APCs.
    • This impairment negatively affects the activation of naïve T cells, demonstrating how viral factors can compromise immune function.R

Summary

  1. Phases of the immune response: Recognition → Activation → Effector → Resolution.
  2. Key players include: APCs, CD4+, CD8+ T cells, and Tregs.
  3. Mechanisms employed consist of cytotoxicity and cytokine activity.
  4. Regulation and memory preserve immune balance and extend long-term protection.