Cytotoxic T cells (also known as CD8+ T cells, cytotoxic T lymphocytes (CTLs), killer T cells) are one of the two major types of T cells, the other are helper T cells. Cytotoxic T cells kill cells infected by virus, bacteria and tumors. Cytotoxic T cells recognize antigens with T cell receptors (TCR) expressed on the surface. In order to bind antigens, the TCR must first be presented with broken-down peptides of the antigen by an antigen presenting cell (APC). The APCs present the antigen with major histocompatibility complexes (MHC) and it is MHC class I molecules on the surface of APCs which present antigens to cytotoxic T cells. Cytotoxic T cells are also called CD8+ T cells because they express the co-receptor CD8 on the surface which also binds to a portion of MHC class I during T cell/antigen presenting cell interactions. CD stands for cluster of differentiation in the nomenclature used to define white blood cells based on cell surface molecules.
An activated cytotoxic T cell has recognized its antigen and has three main mechanisms to kill infected or malignant cells. Firstly, it secretes cytokines such as TNF-α and IFN-γ that have anti-tumor and anti-viral effects. Cytotoxic T cells also produce and release cytotoxic granules, which contain two families of proteins, perforin and granzymes. Perforin causes the membrane of the target cells to form a pore, allowing the granzymes to enter. Granzymes are serine proteases, enzymes that cleave proteins inside the cell, which stops the production of viral proteins and also results in apoptosis of the target cell. The third mechanism of action of cytotoxic T cells on infected cells is the expression of FasL of the cell surface, which binds to the Fas receptor on the target cell surface. Next the Fas molecules trimerise, which causes signalling molecules to be pulled together, activating the caspase cascade, which also results in apoptosis of the target cell.
Cytotoxic T cells can contribute to overactive immune response that leads to immune-related damage. The release of TNF-α and IFN-γ by cytotoxic T cells can lead to a cytokine storm.
Antiviral immune responses are sometimes associated with alterations in normal ratios of helper T cells (CD4 lymphocytes) to cytotoxic T cells (CD8 lymphocytes), called the CD4:CD8 ratio. An inverted CD4:CD8 ratio was found in primary HIV-1 infection. A lower CD4:CD8 was associated with a progressive decrease in immunity in patients with CMV an HIV and suggested as a marker of immunosenescence. A study on COVID-19 patients found no alteration of CD4:CD8 ratio but an increase in the CD8 molecule, suggesting an overexpression of CD8 co-receptor and hyperactivation of cytotoxic T cells in response to the SARS-CoV-2 virus.
Functional exhaustion of cytotoxic T cells is correlated with progression of disease caused by viral infection, chronic infection and tumorigenesis. Patients with SARS-CoV-2 infection (COVID-19 disease) showed a decrease in natural killer (NK) cells and cytotoxic T cells, associated with increased expression of NKG2A. NKG2A is an inhibitory receptor that can induce NK cell and cytotoxic T cell exhaustion when expressed on these cells. Recovering COVID-19 patients showed restored levels of NK and cytotoxic T cells (CD8+ T cells) and reduced levels of NKG2A. NKG2A was suggested as a target for pharmacological intervention for COVID-19 to prevent exhaustion of cytotoxic T cells.