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CD8+ T Cells: Understanding the Role of Cytotoxic T Cells in Immunity

CD8+ T Cells: Understanding the Role of Cytotoxic T Cells in Immunity

CD8+ T cells, also known as cytotoxic T lymphocytes (CTLs), are a critical component of the immune system. They play a vital role in defending the body against viral infections, intracellular pathogens, and tumor cells. This article will delve into the biology of CD8+ T cells, their mechanisms of action, and their clinical relevance, particularly in immunotherapy and infectious disease control.

What Are CD8+ T Cells?

CD8+ T cells are a subset of T lymphocytes that express the CD8 glycoprotein on their surface. This marker distinguishes them from other T cells, such as CD4+ helper T cells. CD8+ T cells are often referred to as killer T cells because of their ability to recognize and destroy infected or cancerous cells.

Differentiation and Activation


CD8+ T cells are initially naive when they emerge from the thymus. They require antigen presentation by antigen-presenting cells (APCs), typically dendritic cells, for activation. The key to their activation lies in recognizing foreign antigens presented by MHC Class I molecules on the surface of infected cells. This interaction, along with costimulatory signals, drives their differentiation into effector cytotoxic T cells.


Step
Description
Antigen Recognition
CD8+ T cells recognize antigens bound to MHC Class I.
Costimulation
Costimulatory signals enhance activation (e.g., CD28).
Cytotoxic Effector Phase
CD8+ T cells differentiate and acquire cytotoxic functions.

Mechanisms of Cytotoxicity

Once activated, CD8+ T cells execute their primary function: killing infected or abnormal cells. This process involves multiple pathways and effector molecules.


Direct Killing Through Perforin and Granzymes


CD8+ T cells induce apoptosis (programmed cell death) in target cells via two primary mechanisms:


1. Perforin-Granzyme Pathway:


  • Erforin forms pores in the target cell membrane.
  • Granzymes, which are serine proteases, enter through these pores and initiate a cascade leading to apoptosis.


    • 2. Fas-FasL Pathway:


    1. CD8+ T cells express Fas Ligand (FasL), which binds to Fas receptors on target cells, triggering a cell death signal.
    Cytotoxic Pathway
    Mechanism
    Perforin-Granzyme
    Perforin forms pores, and granzymes induce apoptosis.
    Fas-Fas Ligand Interaction
    FasL on T cells binds Fas receptors, triggering cell death.

    Cytokine Secretion

    In addition to direct killing, CD8+ T cells secrete cytokines that enhance the immune response. These include: 

    CD8+ T Cells in Viral Infections

    CD8+ T cells are crucial for the elimination of virus-infected cells. During viral infections, viral peptides are presented by MHC Class I molecules on infected cells. CD8+ T cells recognize these antigens and initiate their cytotoxic function.


    Examples of Viral Targets


  • HIV: CD8+ T cells can control the virus by killing infected cells, although HIV mutates to evade detection.
  • Influenza: CTLs are responsible for clearing influenza-infected cells during the acute phase of infection.
    • Virus
    Role of CD8+ T Cells
    Control viral load by killing infected cells, but virus evades CTLs.
    Clear infected cells during the acute phase of infection.

    Memory CD8+ T Cells

    After an infection is resolved, some CD8+ T cells become memory cells. These long-lived cells remain in the body, ready to rapidly respond to future infections by the same pathogen.

    CD8+ T Cells and Cancer Immunity


    CD8+ T cells are central to the immune system's ability to detect and destroy tumor cells. Tumor cells often present tumor-associated antigens (TAAs) via MHC Class I molecules. CD8+ T cells can recognize these antigens and kill the tumor cells, playing a vital role in immune surveillance and cancer immunotherapy.


    Tumor Immune Evasion

    Tumors develop mechanisms to evade immune detection, such as:

    • Downregulation of MHC Class I molecules: Reducing the visibility of tumor antigens to CD8+ T cells.
    • Immunosuppressive environments: Tumors secrete cytokines like TGF-β that inhibit CD8+ T cell function.

    Immunotherapy: Enhancing CD8+ T Cell Function

    In cancer treatment, immunotherapies such as checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4) boost CD8+ T cell activity. These therapies block inhibitory signals that limit T cell activation, enabling CD8+ T cells to effectively target tumors.


    Checkpoint Inhibitor

    Mechanism of Action

    Blocks PD-1, allowing sustained CD8+ T cell activity.

    Increases T cell activation by blocking inhibitory signals.

    CD8+ T Cells in Immunotherapy

    The therapeutic use of CD8+ T cells has garnered significant attention in recent years. Several approaches are currently in use or under development to enhance their cytotoxic potential against diseases such as cancer.


    Adoptive T Cell Transfer (ACT)


    Adoptive T cell transfer involves isolating T cells from a patient, expanding them in the lab, and reintroducing them into the body to fight cancer. Chimeric Antigen Receptor (CAR) T cell therapy is a form of ACT where T cells are genetically modified to target specific antigens on tumor cells.


    Immunotherapy Type
    Description
    Enhance CD8+ T cell activity by blocking inhibitory pathways.
    Adoptive T Cell Transfer (ACT)
    T cells are expanded and reinfused to target cancer cells.
    CAR-T Cell Therapy
    T cells are genetically modified to target specific tumor antigens.

    Therapeutic Vaccines


    Therapeutic vaccines aim to stimulate the immune system, including CD8+ T cells, to target and destroy cancer cells. These vaccines deliver tumor-associated antigens (TAAs) to activate CD8+ T cells.

    Conclusion

    CD8+ T cells are pivotal in both fighting infections and combating cancer. Their ability to recognize and destroy infected or abnormal cells makes them a critical component of the immune system. The use of CD8+ T cells in immunotherapy, particularly through checkpoint inhibitors and adoptive T cell transfer, has revolutionized the treatment of several cancers. However, challenges remain in overcoming tumor immune evasion and enhancing memory responses. Ongoing research continues to expand our understanding of CD8+ T cells and their therapeutic potential.

    References

  • Joshi, N.S. and Kaech, S.M., 2008. Effector CD8 T cell development: A balancing act between memory cell potential and terminal differentiation. The Journal of Immunology, 180(3), pp.130-134.
  • Gallimore, A., and Godkin, A., 2013. Evasion of cytotoxic T lymphocytes by tumor cells. Cancer Immunology, Immunotherapy, 62(9), pp.1391-1401.
  • Schumacher, T.N. and Schreiber, R.D., 2015. Neoantigens in cancer immunotherapy. Science, 348(6230), pp.69-74.
  • Lim, A., et al., 2016. Checkpoint inhibitors in immunotherapy. Nature Reviews Immunology, 16(9), pp.512-524.
  • Wherry, E.J. and Kurachi, M., 2015. Molecular and cellular insights into T cell exhaustion. Nature Reviews Immunology, 15(8), pp.486-499.
  • Restifo, N.P., et al., 2012. Adoptive immunotherapy for cancer: harnessing the T cell response. Nature Reviews Immunology, 12(4), pp.269-281.
  • Klebanoff, C.A., et al., 2016. The plasticity of T cell function during cancer immunotherapy. Nature Reviews Immunology, 16(11), pp.713-723.
    • 23rd Sep 2024 Zainab Riaz

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