Cytotoxic CD8+ T cell

The cytotoxic ^CD8+Tcell (cytotoxic T lymphocyte - CTL) belongs to the T lymphocytes (T from thymus) and are the central effector cells in the defense against intracellular pathogens, especially viruses or tumor cells. They recognize foreign and self-proteins.

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

Furthermore, the cytotoxic ^CD8+Tcells undergo positive or negative selection in the thymus. This positive/negative selection enables cytotoxic ^CD8+ T cells to recognize and attack foreign antigens (e.g. infected body cells or tumour cells) on the one hand and to tolerate the body's own antigens on the other (immunotolerance). This selection and other peripheral control mechanisms can ensure that no activated autoaggressive cytotoxic T cells are produced, thus preventing autoimmune reactions (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. This means that 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). Infected or malignant cells are also recognized by the highly specific T cell receptor via the binding sites of the MHC-I binding complex. MHC-I structures are expressed on the surface of all nucleated, endogenous cells. Antigens (mostly peptides - self-peptides) are bound to them, which originate from the interior of the respective cell and come from the degradation of larger protein molecules.

Healthy, non-infected body cells present a variable mixture of different, cell-specific "self-peptides". This peptide pattern allows them to identify themselves as "healthy" to the cells of the immune system. The T-cell receptors (TCR) on the cell surface only bind to one specific antigen at a time. Antigens that do not correspond to the specificity of the cytotoxic T cells cannot be recognized by them. The binding of 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 activate caspases in the target cell, which are responsible for triggering programmed cell death, i.e. apoptosis. Furthermore, direct activation of the "death receptor" (= Fas receptor) and cell apoptosis also occur.

At the same time, activated cytotoxic T cells secrete interferon-gamma. This cytokine induces 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, such as viral peptides in a correspondingly virally affected cell. Such viral antigens are loaded onto the MHC-I molecules. As a result, they can be recognized and attacked by specifically imprinted cytotoxic T cells. Cytotoxic T cells are therefore important mediators of the cellular immune response.

If specific tumour antigens are presented by the MHC-I molecules instead of microbial antigens, cytotoxic T cells are enabled 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)

1. Blanco P et al (2005) Cytotoxic T lymphocytes and autoimmunity. Curr Opin Rheumatol 17:731-734. Review.
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
5. Nashan D et al (2018) Primary cutaneous lymphoma - a case series of 163 patients. Dermatologist 69: 1014-1020
6. Sharma RK et al (2015) Regulation of cytotoxic T-lymphocyte trafficking to tumors by chemoattractants: implications for immunotherapy. Expert Rev Vaccines 14:537-549.
7. Weigelin B et al (2011) Cytotoxic T lymphocyte migration and effector function in the tumor microenvironment. Immunol Lat. 138:19-21.