131 Cell-Mediated Immune Response

Clonal Selection and T-Cell Differentiation

Antigens are selected to form clones of themselves, both memory and effector.

Clonal selection is an theory that attempts to explain why lymphocytes are able to respond to so many different types of antigens. T and B cells are able to respond to nearly all of the world’s vast variety of antigens upon presentation. Clonal selection assumes that lymphocytes are selected during antigen presentation because they already have receptors for that antigen.

Clonal Selection

In clonal selection, an antigen is presented to many circulating naive B and (via MHC) T cells, and the lymphocytes that match the antigen are selected to form both memory and effector clones of themselves. This mass production is termed “clonal expansion,” in which daughter cells proliferate into several generations of clones of the original parent cells. The theoretical basis of clonal selection is the assumption that lymphocytes bearing an antigen receptor for an antigen exist long before antigen presentation occurs, explained by the idea of random mutations (VDJ recombination) that occur during lymphocyte maturation. During antigen presentation, pre-existing lymphocytes that bear that antigen receptor are merely selected because they can bind with that antigen. It is also assumed that most lymphocytes never encounter the antigen for which they bear a receptor.

Clonal selection may also be used during negative selection during T cell maturation. Here, the body’s own epitopes are presented to the infant lymphocytes; those that react are recognized as auto-reactive and destroyed before they (and their future cloned daughter cells) can leave and wreak havoc in the body. This assumes that random mutations resulted in lymphocytes that were autoreactive instead of reactive to non-self antigens.

Following an adaptive immune response, memory cells are able to respond to a new infection of the same pathogen much more quickly than the original effector T cells during the formation of the adaptive immune response. Clonal selection is thought to cause mutations of antigen-binding affinity in memory cells during clonal expansion so that memory cells have greatly increased antigen-binding affinity than the effector cells during the first response. The increased binding affinity may be why memory cells can eliminate a pathogen more rapidly than the original generation of effector cells. This idea is still only a theory, but explains many of the nuances of the adaptive immune system.

Clonal selection of lymphocytes: A hematopoietic stem cell undergoes differentiation and genetic rearrangement to produce lymphocytes in the immune system. Clonal selection of lymphocytes: 1) A hematopoietic stem cell undergoes differentiation and genetic rearrangement to produce 2) immature lymphocytes with many different antigen receptors. Those that bind to 3) antigens from the body’s own tissues are destroyed, while the rest mature into 4) inactive lymphocytes. Most of these will never encounter a matching 5) foreign antigen, but those that do are activated and produce 6) many clones of themselves.

T Cell Differentiation

Following T cell maturation, naive T cells circulate through the circulatory and lymphatic systems of the body until presented with an antigen for which they bear the receptor. T cells are sorted to be either helper, cytotoxic, or regulatory variants during maturation, but may differentiate into subsets following T cell activation. Following antigen presentation, the T cell is activated and begins to differentiate. T cell differentiation happens via the following steps:

1. The activated T cell becomes a large blast cell.
2. The blast cell proliferates by clonal expansion.
3. Cloned daughter cells differentiate into either effector T cells or memory T cells.
4. Cytotoxic effector T cells are finished, but helper T cells continue to differentiate into individual subsets of helper T cells.

Many different subsets of helper T cells perform various functions. The most common subsets are Th1, which mediates cyotoxic T cell activity through cytokine release, and Th2, which presents antigens to B cells. Additionally, Th17, which only differentiates from effector cells if certain cytokines are present, is important in regulating and inhibiting T-reg cell activity. The effector cells are short-lived for the duration of the adaptive immune response while memory cells are long-lived and are the basis of the secondary immune response.

Specific T-Cell Roles

T helper cells assist the maturation of B cells and memory B cells while activating cytotoxic T cells and macrophages.

Many different categories and subsets of T cells perform various roles for the immune system. Differentiation for most categories of T cells occurs during the the T cell maturation, but memory cell and helper T subset differentiation occurs after maturation following antigen presentation. The different categories of T cells are the basis for cell-mediated immune system activity.

Helper T Cells

Helper T cells assist other white blood cells in immunologic processes by facilitating cytokines that activate and direct other immune cells. Their primary functions include antigen presentation and activation of B cells, and activation of cytotoxic T cells and macrophages. These cells are also known as CD4+ T cells because they express the CD4 protein on their surfaces. Helper T cells become activated when presented with peptide antigens by MHC class II molecules, which are expressed on the surface of antigen-presenting cells. Once activated, they divide rapidly and secrete regulatory cytokines such as IFN-gamma and certain interleukins. These cells can differentiate into one of several subtypes, including TH1, TH2, TH3, TH17, or TFH, which secrete different cytokines to facilitate a different type of immune response. Differentiation into helper T cell subtypes occurs during clonal selection following T cell activation of naive T cells.

Cytotoxic T cells

Cytotoxic T cells (TC cells, or CTLs) destroy virus-infected cells and tumor cells, and cause much of the damage in in transplant rejection and autoimmune diseases. These cells are also known as CD8+ T cells since they express the CD8 glycoprotein at their surfaces. They recognize their targets by binding to antigens associated with MHC class I, which is present on the surface of nearly every cell of the body. Cytotoxic T cells recognize their antigen on pathogens through their T cell receptor, and kill the pathogen through degranulation and cell-mediated apoptosis. The cytotoxic enzymes and proteases travel to their target cells through a microtubule cytoskeleton. Through IL-10, adenosine and other anti-inflammatory cytokines secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state, which can prevent or reduce the severity of autoimmune diseases.

Memory T Cells

Memory T cells are a subset of antigen-specific T cells that persist long after an infection has resolved. They rapidly proliferate to large numbers of effector T cells upon re-exposure to their antigens, thus providing the immune system with “memory” against past infections. The secondary immune response mediated by memory T cells is much faster and more effective at eliminating pathogens compared to the initial immune response. Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells), which have different properties and release different cytokines. Effector memory cells may be either CD4+ or CD8+, and produce either helper or cytotoxic T cells in a secondary immune response.

Regulatory T Cells

Regulatory T cells (Treg cells), also known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Most Treg cells are CD4+ and arise in the thymus. Naturally-occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.

Natural Killer T Cells

Natural killer T cells (NKT cells – not to be confused with natural killer cells) bridge the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigens presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells perform functions ascribed to both Th and Tc cells (i.e., cytokine production and release of cytolytic/cell killing molecules). They are also able to recognize and eliminate some tumor cells and cells infected with herpes viruses. They are among the least common type of T cell in the body and are found in the highest density in the liver. There is an association between NKT cell deficiency and development of autoimmune diseases and chronic inflammatory diseases like asthma, but the exact mechanism of this association is not fully understood.

T cell Activation: T cells become activated upon encountering a pathogen and can become either cytoxic T or helper T cells.

Active and Passive Humoral Immunity

The humoral immune response is the aspect of immunity mediated by secreted antibodies.

The humoral immune response (HIR) is the aspect of immunity mediated by secreted antibodies produced by B cells. Secreted antibodies bind to antigens on the surfaces of invading pathogens, which flag them for destruction. Humoral immunity is so named because it involves substances found in the humors, or body fluids. There are two types of humoral immunity: active and passive.

Active Humoral Immunity

Active humoral immunity refers to any form of immunity that occurs as a result of the formation of an adaptive immune response from the body’s own immune system. Active immunity is long term (sometimes lifelong) because memory cells with antigen-binding affinity maturation are produced during the lymphocyte differentiation and proliferation that occurs during the formation of an adaptive immune response. It also refers to the effector functions of antibodies, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.

Active immunity can either be naturally-occurring or passive. Natural active immunity generally occurs as a result of infection with a pathogen, in which memory cells that remember the antigen of the infectious agent remain in the body. Artificial active immunity is the result of vaccination. During vaccination, the body is exposed to a weakened form of a pathogen that contains the same antigens as the live pathogen, but cannot mount an infection against the body in its weakened state. Vaccinations have become an effective form of disease prevention that is especially useful in preventing diseases that would normally have a high risk of mortality during an infection, where relying on natural active immunity would prove dangerous. However, active immunity does not work to protect against all pathogens, because many can mutate and change their antigen structure over time, which enables them to evade the defenses of immunological memory.

Passive Immunity

Passive immunity is the transfer of active humoral immunity in the form of ready-made antibodies from one individual to another. Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases. Unlike active immunity, passive immunity is short-lived (often only for a few months), because it does not involve the production and upkeep of memory cells.

Passive immunity can occur naturally or artificially. Maternal passive immunity is a type of naturally-acquired passive immunity, and refers to antibody-mediated immunity conveyed to a fetus by its mother during pregnancy. IgG is passed through the placenta to the developing fetus, and is the only antibody isotype that can pass through the placenta. Because passive immunity is short-lived, vaccination is often required shortly following birth to prevent diseases such as tuberculosis, hepatitis B, polio, and pertussis; however, maternal antibodies can inhibit the induction of protective vaccine responses throughout the first year of life. This effect is usually overcome by secondary responses to booster immunization. Passive immunity is also provided through the transfer of IgA antibodies found in breast milk, which are transferred to the gastrointestinal tract of the infant, protecting against bacterial infections until the newborn has produced enough matured B cells to synthesize its own antibodies.

Artificially-acquired passive immunity is a short-term immunization achieved by the transfer of antibodies, and can be administered in several forms: as human or animal blood (usually horse) plasma or serum, as pooled human immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, and as monoclonal antibodies (MAb). Passive transfer is used to help treat those with immunodeficiency and for several types of severe acute infections that have no vaccine, such as the Ebola virus. Immunity derived from passive immunization lasts for only a short period of time, and there is potential risk for hypersensitivity reactions and serum sickness, especially from gamma globulin of non-human origin. Passive immunity provides immediate protection, but the body does not develop memory; therefore, the patient is at risk of being infected by the same pathogen later.

Innate and adaptive immunity in the immune system: This chart depicts the different divisions of immunity, including adaptive, innate, natural, artificial, passive (maternal), active (infection), passive (antibody transfer) and active (immunization).