A cytotoxic T cell (also known as T_C or killer T cell) is a sub-group of T lymphocyte (a type of white blood cell) which is capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses (or other pathogens), or are otherwise damaged or dysfunctional.

Most cytotoxic T cells express T-cell receptors (TcRs) that can recognise a specific peptide antigen bound to Class I MHC molecules. These T_C cells also express CD8, which is attracted to portions of the Class I MHC molecule. This affinity keeps the T_C cell and the target cell bound closely together during antigen-specific activation. T_C cells with CD8 surface protein are called CD8+ T cells, and CD8+ T cells are generally classified as having a pre-defined cytotoxic role within the immune system.

Cytotoxic T cell development

Hematopoetic stem cells in the bone marrow migrate into the thymus, where they undergo VDJ rearrangement of their beta-chain TcR DNA to form a developmental form of the TcR protein, known as pre-TcR. If that rearrangement is successful, the cells then rearrange their alpha-chain TcR DNA to create a functional alpha-beta TcR complex. This highly-variable genetic rearrangement product in the TcR genes helps create millions of different T cells with different TcRs, helping the body's immune system respond to virtually any protein invader. The vast majority of T cells express alpha-beta TcRs, but some T cells in epithelial express beta-gamma TcRs, which recognize non-protein antigens.

T cells with functionally stable TcRs express both the CD4 and CD8 co-receptors and are therefore termed "double-positive" T cells (CD4+/CD8+). The double-positive T cells are exposed to a wide variety of self-antigens in the thymus and undergo two selection criteria: (1) negative selection, in which those double-positive T cells that bind too strongly to MHC-presented self antigens undergo apoptosis because their propensity to become autoreactive could lead to autoimmunity; and (2) positive selection, in which those double-positive T cells that bind too weakly to MHC-presented self antigens undergo apoptosis because of their inability to recognize MHC-protein complexes. Only those T cells that bind to the MHC-self-antigen complexes weakly are positively selected. Those cells that survive positive and negative selection differentiate into single-positive T cells (either CD4+ or CD8+).

Cytotoxic T cell activation

With the exception of some cell types such as non-nucleated cells (including erythrocytes), Class I MHC is expressed by all host cells. When these cells are infected with a virus (or another intracellular pathogen), the cells "break down" foreign proteins via antigen processing. These result in peptide fragments, some of which can bind to MHC Class I and become antigenic to CD8+ T cells.

Cytotoxic T cells are activated when their TcR strongly interacts with a peptide-bound MHC class I molecule. Once activated they undergo clonal expansion (with the help of Interleukin-2 provided by helper T cells. They then travel throughout the body in search of antigen-positive somatic cells.

When exposed to infected/dysfunctional somatic cells, T_C cells release the cytotoxins perforin and granulysin, which forms pores in the target cell's plasma membrane; this causes ions and water to flow into the target cell, making it expand and eventually lyse. T_C also release granzyme, a serine protease, that can enter target cells via the perforin-formed pore and induce apoptosis (cell death).

A second way to induce apoptosis is via cell-surface interactions between the T_C and the infected cell. When a T_C is activated it starts to express the surface cytokine FAS ligand, which can bind to Fas molecules on the target cell. This Fas-Fas ligand interaction is the main route to dispose of unwanted T lymphocytes during their development.

Cytotoxic T cell role in disease pathogenesis

• Hepatitis B virus (HBV) infection

During HBV infection cytotoxic T cells play an important pathogenetic role. They contribute to nearly all of the liver injury associated with HBV infection and, by killing infected cells and by producing antiviral cytokines capable of purging HBV from viable hepatocytes, cytotoxic T cells also eliminate the virus. Recently platelets have been shown to facilitate the accumulation of virus-specific cytotoxic T cells into the infected liver.

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