The human body is protected by both innate and adaptive immune systems. Adaptive immunity is associated with cell-mediated and antibody-mediated immune responses. For antibody-mediated immune response, immunoglobulins are produced by B lymphocytes.
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Whereas, cell-mediated immune response is generated by T lymphocytes and is divided into two classes, namely, helper (CD4+) and cytotoxic T cells (CD8+). Cytotoxic T cells can directly kill intracellular pathogens and remove mutated and cancerous cells. This article is focused on the structure and various roles of cytotoxic T-cells which protect against harmful pathogens.
Structure and Activation of Cytotoxic T Cells
Two of the most important components of cytotoxic T cells are T cell receptors on the cell surface and lytic granules in the cytoplasm. The lytic granules are a type of lysosomes that contains two cytotoxic proteins, i.e., granzyme (serine proteases) and perforin. The T cell receptors are membrane-bound polypeptide structures that are produced by alpha and beta chains connected via disulfide bonds.
The T cell receptors have three distinct regions, a) antigen-binding site at its extracellular section containing a positively charged transmembrane region, which binds to the plasma membrane, and short intracytoplasmic tail, b) alpha and beta chain region (extracellular portion), which comprises one variable and one constant region, c) hypervariable domain of both chains forms the antigen-binding site.
Antigens are produced upon degradation of foreign proteins or harmful pathogens by antigen-presenting cells. When antigens bind with the major histocompatibility complex class 1 (MHC), they are recognized by cytotoxic T cells. MHC plays a vital role in immune response, i.e., it is associated with T cell activation and is involved with the maturation of T cells in the thymus.
The activation of cytotoxic T cells is associated with the recognition of an antigen on MHC 1 by T cell receptor and a co-stimulatory signal. The co-stimulatory signal is involved with the interaction between the CD28 molecule present on the surface of T cells and B7 protein which exists on antigen-presenting cells.
Some of the Functional Roles of Cytotoxic T Cells
A virus depends on host cell machinery for its replication. In a virus-infected cell, the expression of antigen is important for the activation of cytotoxic cells. Upon activation, naive cytotoxic cells are converted into effecter cytotoxic cells which release lytic granules. Perforin polymerizes and produces transmembrane pore, which alters the structure of the infected host cell.
Subsequently, granzyme B enters the target cell via transmembrane pores to activate caspases, which induces programmed cell death in the infected host cell. Hence, apoptosis of host cells leads to the elimination of the virus.
Even though cytotoxic T cells mostly use perforin and granzyme B to induce apoptosis, occasionally it also uses Fas Ligand on cell membranes to bind Fas present on the infected cell. This binding activates caspases which leads to apoptosis in the infected host cell.
Besides viruses, cytotoxic T cells are also involved with the elimination of bacteria, parasites, and fungi which might be present both inside or outside the cell. In this case, cytotoxic T cells use the protein called granulysin to disrupt the structure of the cell membrane and promote lysis of the cell.
Additionally, cytotoxic CD8 T cells also restrict the spread of cytosolic pathogens by various means. Most cytotoxic CD8 T cells are also involved with releasing cytokines IFN-γ, TNF-α, and TNF-β. These cytokines are associated with the host defense mechanism in multiple ways. For example, IFN-γ directly inhibits the replication of viruses and triggers an increased expression of MHC class I.
The overexpression of MHC class I maximizes the chance of infected cells being recognized for cytotoxic attacks. Further, IFN-γ also stimulates macrophages and designates them to sites of infection both as effector cells and as antigen-presenting cells. This is extremely important for the removal of intracellular protozoan pathogens such as Toxoplasma gondii.
Another important role of IFN-γ in host defense is that it decreases the tryptophan concentration within responsive cells. This leads to the effective elimination of intracellular parasites by starvation. TNF-α or TNF-β assists IFN-γ for macrophage activation.
Cytotoxic T cells are not only selective but may act like a serial killer to specific antigens (targets). In this regard, researchers performed an experiment where cytotoxic T cells were offered an equal mixture of two target cells, one bearing a specific antigen whereas the other was not. They found that cytotoxic T cells eliminated only the target cell bearing the specific antigen.
Further, researchers observed that cytotoxic T cells bind to several different target cells, after which, they reorient their secretory apparatus and kill them one by one. Hence, this mode of action enables them to kill a single infected cell without causing any damage to the surrounding healthy tissues. This mechanism is highly advantageous because it protects tissues where cell regeneration does not occur, for example, neurons of the central nervous system.
Further, the cytotoxic T cells can kill targeted cells rapidly. This is because they store inactive cytotoxic proteins within the lytic granule. During the first encounter between a naive cytotoxic precursor T cell and a specific antigen, cytotoxic proteins are produced and are loaded into the lytic granules.
Ligation of T-cell receptor similarly elicits synthesis of perforin and granzymes in effector CD8 T cells. This ensures a steady supply of lytic granules which allows a single CD8 T cell to kill many targets in succession.
Clinical Significance of Cytotoxic T cells
Patients undergoing organ transplants often succumb to viral infection and drug toxicity. Researchers are in the process of developing T cell immune therapy to control new viral infections, the revival of latent viruses because of immunosuppressive drugs, and reduce unwanted drug toxicity.
Further, cytotoxic T cells have been also studied for the treatment of autoimmune diseases. This is because these cells have the inherent ability to control inflammation and release anti-inflammatory cytokines.
- Caminero, F. et al. (2021). Histology, Cytotoxic T cells. StatPearls Publishing. [Online] Available at: https://www.ncbi.nlm.nih.gov/books/NBK559279/
- Farhood, B. et al. (2019). CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review. Journal of Cellular Physiology. 234(6), pp.8509-8521. doi: 10.1002/jcp.27782.
- Andersen, H.M. et al. (2006). Cytotoxic T cells. Journal of Investigative Dermatology, 126(1), pp. 32-41.
- Janeway, C.A. et al. (2001). Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science. T cell-mediated cytotoxicity. [Online] Available from: https://www.ncbi.nlm.nih.gov/books/NBK27101/