Introduction

The innate and adaptive immune systems form 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.[1] Antibody-mediated and cell-mediated responses carry out adaptive immunity. 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 directly killing intracellular and extracellular pathogens and eliminating mutated and cancerous cells. These immune responses are generated by T-cells when they recognize an antigen, which is exposed 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 to a protein called the major histocompatibility complex (MHC).[2] MHC proteins aid in T-cell activation and have 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 for maturation. They enter the thymus at the corticomedullary junction and move towards the cortex while undergoing developmental changes to accumulate in the subcapsular zone. Initially, the newly arrived intrathymic immature T-cells are known as double-negative cells because they lack expression of CD4 or CD8, but during maturation, they develop both CD4 and CD8 receptors and are then called double-positive cells. In the thymus, these immature double-positive cells are presented with various antigens, and a small subset (1%-5%) binds to antigens connected to MHC types 1 or type 2. The rest of the double-positive cells undergo apoptosis.[3] The T-cells that bind to MHC type 1 molecules become CD4-/CD8+ (cytotoxic T-cells), and the T-cells that bind to MHC type 2 molecules become CD4+/CD8- (helper T-cells). This process is called positive selection. Positively selected T-cells enter the medulla, where they undergo negative selection. This process involves eliminating T-cells whose receptors bind strongly to self-antigens or self-MHC proteins (avoiding autoimmunity).[2]  

Structure

T-cell receptors (TCRs) on the cell surface and lytic granules in the cytoplasm are cytotoxic T-cells' two most important components. The lytic granules are modified lysosomes containing two types of cytotoxic proteins: serine proteases (granzymes) and perforins. These cytotoxic 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. These receptors have 3 distinct regions: an extracellular part, which has an antigen-binding site; a positively charged transmembrane area, which anchors it to the plasma membrane; and a short intracytoplasmic tail. Alpha- and beta-chain regions, which form the extracellular portion, are comprised of one variable and one constant region. The hypervariable domain of both chains forms the antigen-binding site. During T-cell development in the thymus, alpha- and beta-chain gene segments rearrange to develop antigen diversity.[2] 

The cytotoxic TCR is associated with transmembrane glycoprotein CD8, a co-receptor. Activating a cytotoxic T-cell involves recognizing an antigen (bound to MHC class 1) by a T-cell receptor and a costimulatory signal. The costimulatory signal is between the CD28 molecule on the T-cell surface and a protein known as B7 on antigen-presenting cells.[4]

Helper T-cells have two functions—producing cytokines and inducing B-cells to produce antibodies. There are several subsets of helper T-cells, each secreting a different cytokine profile. Follicular helper-T cells are one of these subtypes, and their function is to induce germinal centers to produce memory B-cells, plasma cells, and antibodies with different isotopes. Regulatory helper T-cells, another helper T-cell subset, suppress the activation of many types of immune cells that react to self-antigens, such as autoreactive lymphocytes, natural killer cells, and antigen-presenting cells. This helps prevent autoimmune disease, transplant rejection, and allergic reactions.

Function

Viruses depend on host cell metabolic machinery to survive. Their intracellular location protects them from antibodies. Expression of antigens on virally infected cells activates cytotoxic T-cells, inducing apoptosis of host cells and subsequent virus death in infected cells.[2] Upon activation, naïve cytotoxic cells become effector cytotoxic cells. These effector cytotoxic cells release perforin, which polymerizes to form a transmembrane pore, allowing for membrane destruction of infected cells. Granzyme B, a serine protease, also enters the target cell through these pores to activate caspases, which cause the cell to undergo apoptosis. Some cytotoxic T-cells form memory CD8 T-cells after their initial interaction with a pathogen.[5] Although cytotoxic T-cells primarily use perforin and granzyme B to induce apoptosis in the target cell, they sometimes use the Fas ligand on their cell membranes to bind Fas antigen on the infected cell. This binding activates caspases, and the cell undergoes apoptosis.[2]

Cytotoxic T-cells also destroy bacteria, parasites, and fungi by the secretion of granulysin, which is released upon contact with these microbes. Cytotoxic T-cells generally need antigens to be presented on MHC molecules for intracellular pathogens, but they recognize extracellular pathogens without MHC molecules.[6]

Pathophysiology

The inability to eliminate pathogens in chronic infection is described as an exhaustion of T-cells. This cytotoxic function loss is caused by ongoing exposure to an antigen, which induces the expression of inhibitory receptors on CD8 T-cells. These inhibitory receptors impair T-cell receptor signaling pathways, blocking receptor activation and propagation.[7] This is the case in chronic hepatitis C infection. The persistence of the hepatitis C virus causes constant stimulation of CD8 T-cells, eventually leading to the expression of inhibitory receptors and ineffectiveness of the cytotoxic cells, and additional therapy is required to reactivate these cytotoxic cells.[8]

Cytotoxic T-cells can contribute to the pathology of autoimmune disease. One example is the development of type 1 diabetes due to the destruction of pancreatic cells by cytotoxic T-cells. Inflammatory infiltrates in these patients predominantly contain CD8+ T-cells, among other inflammatory cells.[9] Another example is polymyositis, in which the destruction of muscle fibers is caused by perforin and granzyme, which is evident by heavy infiltration of CD8+ T-cells in the endomysial inflammatory infiltrate.[10] Similar mechanisms appears to be responsible for the development of other autoimmune diseases.[11] 

Clinical Significance

Viral infection, drug toxicity, and rejection are unwanted outcomes in transplant patients. T-cell immune therapy is under investigation as a possible strategy to control new viral infections and activation of latent viruses due to immunosuppressive drugs. One immunotherapeutic strategy being studied is transferring virus-specific T-cells from healthy donors to immunocompromised ones. Another study area uses inhibitory cytotoxic T-cells that modify the activation of immune pathways and antigen-presenting cells to prevent autoimmunity.[12][13]