Cytotoxic t-lymphocyte

The cytotoxic T lymphocyte (CTL) belongs to the T lymphocytes (T of thymus) and is the central effector cell in the defence against intracellular pathogens, especially viruses and tumour cells. They recognize foreign and self proteins.

The T cells are formed in the bone marrow and migrate into the thymus. Here they form certain protein patterns on their surface, the highly specific MHC receptors.

Furthermore, the cytotoxic T cells undergo positive or negative selection in the thymus. This positive/negative selection enables cytotoxic T-cells to recognize and attack foreign antigens (e.g. infected body cells or tumor cells) on the one hand and to tolerate the body's own antigens on the other hand (immuno tolerance). Through this selection and through further peripheral control mechanisms it can be ensured that no activated autoagressive cytotoxic T cells are produced, so that autoimmune reactions are prevented (Blanco P et al. 2005).

During the developmental process of T cells in the thymus, a large number of cytotoxic T cells with different specificities are produced. However, only those T-cells that bind foreign peptides, but not the body's own, survive the selection process. This selection process leads to about 95% of immature T cells being converted to programmed cell death(apoptosis). 5% of the cells are available to the organism as naive cytotoxic T cells.

In order to generate activated and thus fully functional cytotoxic T cells from naive cytotoxic T cells, the antigen-specific interaction of the naive cytotoxic T cells with professional antigen-presenting cells (mostly mature dendritic cells) is still necessary. Thus, mature dendritic cells are able to activate naïve CD8+ cytotoxic T cells via costimulatory signals. After activation, these cytotoxic T cells are able to recognize and eliminate infected or (malignant) transformed cells. These tumor protective properties can be used therapeutically (Sharma RK et al. 2015).

In order for the cytotoxic T cell to achieve its complete function and to be able to form memory cells, additional interactions with CD4+ T helper cells are necessary (Hoyer S et al. 2014). After their immunological imprint, cytotoxic T cells circulate through blood, lymph nodes, skin and other organs.

In general, T cells can only interact with antigens that are presented via MHC receptors. Thus, free antigens can only be recognized by cytotoxic T lymphocytes if they are actively presented by so-called antigen presenting cells (so-called MHC restriction). The recognition of infected or malignant cells by means of the highly specific T cell receptor is also carried out via the binding sites of the MHC-I binding complex. MHC-I structures are expressed on the surface of all nucleated endogenous cells. Antigens (usually peptides - self-peptides), which originate from the interior of the respective cell and are derived from the degradation of larger protein molecules, are bound to them.

Healthy, non-infected body cells present a variable mixture of different, cell-specific "self-peptides". This peptide pattern enables them to identify themselves as "healthy" before the cells of the immune system. The T-cell receptors on the cell surface only bind to a specific antigen. Antigens that do not correspond to the specificity of the cytotoxic T cells cannot be recognized by them. The binding of the activated cytotoxic T-cells to their specific MHC-I peptide complex leads to the release of proapoptotic and cytotoxic substances such as perforins, granulysin and granzymes. After perforins have made the cell membrane of the target cell more permeable, granzymes in the target cell activate caspases that are responsible for inducing programmed cell death, i.e. apoptosis. In addition, the direct activation of the "death receptor" (= Fas receptor) and cell apoptosis also occurs.

At the same time, activated cytotoxic T cells secrete interferon-gamma. This cytokine induces an increased expression of MHC-I proteins in the target cells (de Araújo-Souza PS et al. 2015). This MHC-I induction in turn leads to an increased presentation of intracellularly degraded peptides, including viral peptides in a correspondingly virally infected cell. Such viral antigens are loaded onto the MHC-I molecules. This enables them to be recognised and attacked by specifically imprinted cytotoxic T cells. Cytotoxic T cells are thus important mediators of the cellular immune response.

If instead of microbial antigens specific tumor antigens are presented by the MHC-I molecules, cytotoxic T cells are able to recognize and attack them (Weigelin B et al. 2011).

A characteristic molecular marker for cytotoxic T cells is the CD8 protein, which binds to the MHC-I molecules. Together with the actual T-cell receptor, CD3 molecules and various other proteins, the protein binds to the MHC-I molecules. proteins, it forms the T-cell receptor complex. The typical immunohistological marker pattern for cytotoxic T-cells is characterized by the positivity for CD8, TIA-1, granzyme and perforin (Nashan D 2018)

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2. Chang HF et al (2017) Preparing the lethal hit: interplay between exo- and endocytic pathways in cytotoxic T lymphocytes. Cell Mol Life Sci 74:399-408.
3. de Araújo-Souza PS et al. (2015) Epigenetic control of interferon-gamma expression in CD8 T cells. J Immunol Res 2015:849573.
4. Hoyer S et al (2014) Concurrent interaction of DCs with CD4 and CD8 T cells improves secondary CTL expansion: It takes three to tango. European J Immunol 44: 3543
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