The innate and adaptive immune system forms the basis of immunity in human beings. Innate immunity is a generalized and non-specific response to pathogens, while adaptive immunity induces pathogen-specific, more sophisticated, and long term responses. Adaptive immunity is carried out by antibody-mediated and cell-mediated response. The antibody-mediated response involves the production of immunoglobulin by B lymphocytes. The response generated by T cells is called a cell-mediated response. There are two classes of T lymphocytes, helper, and cytotoxic T cells, also called CD4+ and CD8+ T cells, respectively.
Helper T cells activate macrophages and cytotoxic cells and stimulate antibody synthesis in B lymphocytes. Cytotoxic cells are involved in the direct killing of intracellular pathogens, and the elimination of mutated and cancerous cells. These immune responses are generated by T cells when they recognize an antigen, which is presented to them by antigen-presenting cells. The antigen is a peptide fragment generated by antigen-presenting cells when they degrade the foreign protein. To be recognized by a T cell, the antigen must bind a protein called the Major histocompatibility complex (MHC). Cytotoxic T cells recognize antigen bound to MHC protein type 1. MHC not only aid in T cell activation, but it also has a vital role in the maturation of T cells in the thymus.
T lymphocytes originate from hematopoietic stem cells in the bone marrow and migrate to the thymus to maturate. They enter thymus at corticomedullary junction and move towards the cortex while undergoing developmental changes to accumulate in the subcapsular zone. These newly arrived intrathymic immature T cells are known as double-negative cells because they lack expression of CD4, CD8, and T cell receptors on their surface. These cells differentiate to express CD4 and CD8 on their surface and have a T cell receptor. Due to the expression of both surface markers, these cells are referred to as double-positive cells. These immature T cells become exposed to antigens attached to MHC, cells capable of identifying these antigens are selected for further differentiation, and the rest of the cells undergo apoptosis. This process is called positive selection. Positively selected T cells enter medulla, where they undergo negative selection. This process involves the elimination of T cells whose receptor binds strongly to the self-antigen or a self MHC protein. Cells become single positive based on the type of MHC protein they bound during the maturation process.
T cell receptors on the cell surface and lytic granules in the cytoplasm are the two most important components of cytotoxic T cells. The lytic granules are modified lysosomes containing two cytotoxic proteins, the perforin and serine proteases called granzyme. These cytotoxic effecter proteins are secreted when the T cell is activated. T cell receptors are membrane-bound polypeptide structures formed by alpha and beta chains linked by a disulfide bond. It has three distinct regions; an extracellular part which has an antigen-binding site, a positively charged transmembrane region which anchors it to the plasma membrane, and short intracytoplasmic tail. Alpha and beta chain region which form the extracellular portion is composed of one variable and one constant region. The hypervariable domain of both chains forms the antigen-binding site. During T cell development in thymus alpha and beta chain gene segment rearrange to develop antigen diversity.
Cytotoxic TCR is associated with transmembrane glycoprotein CD8, which acts as a co-receptor. Activation of a cytotoxic T cell involves recognition of antigen on MHC class 1 by T cell receptor and a co-stimulatory signal. The co-stimulatory signal is an interaction between the CD28 molecule on the T cell surface and a protein known as B7 on antigen-presenting cells.
Virus depends on the host cell metabolic machinery to survive. Its intracellular existence protects from antibodies action. Expression of antigen on virally infected cells forms the important source of cytotoxic cell activation, which induces apoptosis of host cells leading to the death of a virus. Upon activation, naïve cytotoxic cells convert into effecter cytotoxic cells. These effecter cytotoxic cells release lytic granules. Perforin polymerizes to form a transmembrane pore, which disrupts the integrity of the infected cell. Granzyme B also enters the target cell through these pores to activate caspases, which cause the cell to undergo programmed cell death.DNA degradation needs activation of special nuclease called caspase-activated deoxyribonuclease. Cytotoxic T cells utilize the same effecter protein to kill cancerous cells when the immunogenic antigens activate them on these cells. Some of the cytotoxic T cells form memory CD8 T cells after their initial interaction with a pathogen. Although cytotoxic T cells mostly use perforin and granzyme B to induce apoptosis in the target cell, sometimes cytotoxic T cells use Fas Ligand on cell membranes to bind Fas present on the infected cell. This binding activates caspases, and the cell undergoes apoptosis.
Cytotoxic T cells appear to be involved in the killing of some bacteria, parasite, and fungi. Granulysin is the protein involved in the killing of these pathogens, which may be present inside or outside the cell. The killing of extracellular microbes involves the release of granulysin when CTL recognize these microbes when they directly get in contact with them. When a microbe is present inside the cell CTL release granulysin intracellularly, this recognition is usually not dependent on MHC. Grnulysin disrupts the integrity of cell membrane inducing lysis of the cell.
Human cytotoxic T cell responds to HIV infection by releasing cytolytic proteins and chemokines. Although HIV targets CD4 T cells, under the threat of the human immune system, HIV adopts several mechanisms to escape the cytolytic effect of cytotoxic T cells. Mutation in amino acid synthesis leads to variation in antigen expression and decreased recognition of infected cells by CD 8 cells. Several HIV proteins decrease MHC type 1 expression and have a pro-apoptotic effect of CD 8 cells. These immune evasion adaptations cause persistent HIV infection due to weak cytolytic response by CD 8 cells.
The inability to eliminate pathogens in chronic infection is described as an Exhaustion of T cells. This cytotoxic function loss is induced by the expression of inhibitory receptors on CD8 T cells. These inhibitory receptors impair T cell receptor signaling pathways, blocking its activation and propagation. Cytotoxic T cells contribute to the development of type 1 diabetes by directly damaging islet cells. Inflammatory infiltrates found in these patients predominantly contain CD8 T cells, among many other inflammatory cells. Cytotoxic T cells react against the antigen present on the pancreatic islet cells. The same mechanism appears to be responsible for the development of autoimmune diseases in human beings. Autoreactive cytotoxic T cells react against the self-antigen presented to them by the antigen-presenting cells. They use their cytotoxic killing mechanisms and release cytokines to effectively destroy the human cells.
Destruction of muscle fibers in polymyositis is executed by perforin and granzyme, which is evident by heavy infiltration of CD8 T cells in the endomysial inflammatory infiltrate. Cytotoxic cells have a vital role in the pathogenesis of Hepatitis C. Persistence of Hep C causes constant stimulation of CD8 T cells. Destruction of hepatocytes on antigen recognition present on them ultimately leads to liver cirrhosis.
Viral infection, drug toxicity, and resistance are unwanted outcomes in transplant patients. T cell immune therapy is under investigation as a possible strategy to control new viral infection and reactivation of latent viruses due to immunosuppressive drugs. This new development could also decrease unwanted drug toxicity and resistance. Cytotoxic T cells have the innate ability to control the inflammation and release anti-inflammatory cytokines is under investigation to treat autoimmune diseases. The inhibitory T cells and anti-inflammatory cytokines could be new therapeutic options available in the future to treat autoimmune disease.
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