127 Adaptive Immunity

Overview of Adaptive Immunity

The adaptive immune system is composed of highly-specialized systemic cells and processes that eliminate or prevent pathogenic growth.

The adaptive immune system, also known as the specific immune system, is composed of highly-specialized systemic cells and processes that eliminate or prevent pathogenic growth. The adaptive immune system works to protect and heal the body when the innate immune system fails. It provides the body with the ability to recognize and remember specific pathogens through their antigens. This mechanism allows the immune system to mount stronger attacks each time the pathogen is encountered, thus preparing itself for future challenges and preventing reinfection by the same pathogen.

Functions of the Adaptive Immune System

The adaptive immune system starts to work after the innate immune system is activated. If an infection progresses despite the inflammation, fever, natural killer (NK) cell and phagocyte activity of the innate immune system, a more coordinated response is required in order to destroy the pathogen. The adaptive immune response occurs a few days after the innate immune response is initiated. The major functions of the adaptive immune system include:

• The recognition of specific “non-self” antigens in the presence of “self” during the process of antigen presentation
• The generation of responses that are tailored to maximally eliminate specific pathogens or pathogen-infected cells
• The development of immunological memory in which each pathogen is “remembered” by a signature antibody, which can then be called upon to quickly eliminate a pathogen should subsequent infections occur.

Formation of Adaptive Immunity

Adaptive immunity is triggered when a pathogen evades the innate immune system for long enough to generate a threshold level of an antigen. An antigen is any molecule that induces an immune response, such as a toxin or molecular component of a pathogen cell membrane, and is unique to each species of pathogen. A typical adaptive immune response includes several steps:

1. The antigen for the pathogen is taken up by an antigen-presenting cell (APC), such as a dendritic cell or macrophage, through phagocytosis.
2. The APC travels to a part of the body that contains immature T and B cells, such as a lymph node.
3. The antigen is processed by the APC and bound to MHC class II receptors and MHC class I receptors on the cell membrane of the APC.
4. The antigen is presented to immature helper T cells and cytotoxic T cells through binding the MHC II (helper T) or MHC I (cytotoxic T) to T-cell receptors.
5. These T lymphocytes mature and proliferate. Helper T cells activate B cells, which proliferate and produce antibodies specific to the antigen, while cytotoxic T cells destroy pathogens that bear the antigen that was presented to them by the APCs.
6. Memory B and T cells are formed after the infection ends.

Immunological Memory

When B cells and T cells are activated, some become memory cells. Throughout the lifetime of an animal, these memory cells form a database of effective B and T lymphocytes. Upon interaction with a previously-encountered antigen, the appropriate memory cells are selected and activated. In this manner, the second and subsequent exposures to an antigen produce a stronger and faster immune response. This is “adaptive” because the body’s immune system prepares itself for future challenges, which can stop an infection by the same pathogen before it can even cause symptoms.

Immunological memory can either be in the form of passive short-term memory or active long-term memory. Passive memory is usually short-term, lasting between a few days and several months, and is particularly important for newborn infants, who are given passive memory from maternal antibodies and immune cells before birth. Active immunity is generally long-term and can be acquired by infection followed by B cells and T cells activation, or artificially acquired by vaccines in a process called immunization.

The memory system does have a few flaws. Pathogens that undergo mutation often have different antigens than those known by memory B and T cells, meaning that different strains of the same pathogen can avoid the memory-enhanced immune response. Additionally, the memory cell function enables the development of hypersensitivity disorders, such as allergies and many chronic diseases (like multiple sclerosis or myasthenia gravis). In these cases, memory cells form for an antigen that elicits an immune response without actually being caused by a pathogen, which leads to immune system mediated-damage to the body from mast cell, antibody, or T-cell mediated activities and inflammation.

Types of Adaptive Immunity

The adaptive immune response is mediated by B and T cells and creates immunity memory.

The adaptive immune system mounts a stronger, antigen-specific immune response after the innate immune response fails to prevent a pathogen from causing an infection. There are two subdivisions of the adaptive immune system: cell-mediated immunity and humoral immunity.

Cell-Mediated Immunity

Cell mediated immunity is controlled by type 1 helper T cells (T_h1) and cytotoxic T cells. These cells are activated by antigen-presenting cells, which causes them to rapidly mature into forms specific to that antigen. T cells then circulate through the body to destroy pathogens in several ways. Helper T cells facilitate the immune response by guiding cytotoxic T cells to pathogens or pathogen-infected cells, which they will then destroy.

Cytotoxic T cells kill pathogens in several ways, including the release of granules that contain the cytotoxins perforin and granzyme, which lyse small pores in the membrane of a pathogen. Then T-cell produced proteases enter the pathogen and induce an apoptosis response within the cell. Helper T cells secrete cytokines  such as interferon-gamma, which can activate cytotoxic T cells and macrophages.

Humoral Immunity

Humoral immunity refers to the component of the adaptive immune response that is caused by B cells, antibodies, and type 2 helper T cells (T_h2), as well as circulating mast cells and eosinophils to a lesser extent. Its name comes from the idea that blood is one of the humors of the body, since antibodies provide passive or active immunity through circulation in the bloodstream.

Type 2 helper T cells are included in the humoral immune system because they present antigens to immature B-cells, which undergo proliferation to become specific to the presented antigen. The B cells then rapidly produce a large number of antibodies that circulate through the body’s plasma.

Antibodies provide a number of functions in humoral immunity. Six different classes of antibodies provide distinct functions and interact with different cells in the immune system. All antibodies bind to pathogens to opsonize them, which makes it easier for phagocytic cells to bind to and destroy the pathogen. They also neutralize the toxins produced by certain pathogens and provide complement pathway activation, in which circulating proteins are combined in a complex cascade that forms a membrane attack complex on a pathogen cell membrane, which lyses the cell.

Mast cells and eosinophils are considered part of the humoral immune system because they can be sensitized towards certain antigens through circulating immunoglobin E (IgE), a specific type of antibody produced by B cells. IgE binds to the mast cells and eosinophils when an antigen is detected, using a type of Fc receptor on the mast cell or eosinophil that has a high-binding affinity with IgE. This binding will cause degranulation and release of inflammatory mediators that start an immune response against the antigen. This process is the reason why memory B cells can cause hypersensitivity (allergy) formation, as circulating IgE from those memory cells will activate a rapid inflammatory and immune response.

Maturation of T Cells

T cells originate from hematopoietic stem cells in the bone marrow and undergo positive and negative selection in the thymus to mature.

T cells belong to a group of white blood cells known as lymphocytes and play a central role in the cell-mediated branch of the adaptive immune system. They are distinguished from other lymphocytes, such as B cells and natural killer cells (NK cells), by the presence of a T cell receptor (TCR) on the cell surface. T cells are produced in the bone marrow but travel to the thymus to mature. T cells can be either helper T cells or cytoxic T cells based on whether they express CD4 (helper) or CD8 ( cytotoxic ) glycoprotein.

Maturation of T Cells

All T cells originate from hematopoietic stem cells in the bone marrow, which are capable of differentiating into any type of white blood cell. Immature T cells that migrate to the thymus are called thymocytes. The earliest thymocytes express neither CD4 nor CD8, and are therefore classed as double-negative (CD4-CD8-) cells. As they progress through their development they become double-positive thymocytes (CD4+CD8+) and finally mature to single-positive (CD4+CD8- or CD4-CD8+) thymocytes that are released from the thymus to peripheral tissues. Typically, these mature thymocytes are still referred to as either “immature” or “naive” because they have not been presented with an antigen. They travel to sites that contain secondary lymphoid tissue, such as the lymph nodes and tonsils, where antigen presentation. This facilitates the development of antigen-specific adaptive immunity.

The thymus contributes fewer cells as a person ages. As its functional mass shrinks by about 3% a year throughout middle age, there is a corresponding fall in the thymic production of naive T cells, leaving clonal expansion of immature T cells to play a greater role in protecting older subjects. The thymus is thus thought to be important in building a large stock of naive T cells soon after birth that can later function without thymus support.

Positive Selection of T Cells

During thymocyte maturation, 98% of T cells are discarded by selection, thich is a mechanism designed to ensure that T cells function without major problems. Positive selection designates T cells capable of interacting with MHC. Double-positive thymocytes (CD4+/CD8+) move deep into the thymic cortex tissue where they are presented with self-antigens. These are expressed by thymic cortical epithelial cells that express both MHC I and MHC II molecules on the surface of cortical cells. Only those thymocytes that interact with MHC I or MHC II will receive a vital “survival signal.” Thosethat can’t interact will undergo apoptosis (cell death). This insures T cell functionality since T cells with non-functional receptors cannot receive antigens and are thus useless to the immune system. If non-functional T cells were allowed into circulation, they would crowd out functional T cells and slow down the rate at which adaptive immune responses are formed. The vast majority of thymocytes die during this process.

A thymocyte’s differentiation into either a helper or cytotoxic version is also determined during positive selection. Double-positive cells (CD4+/CD8+) that are positively selected on MHC class II molecules will eventually become CD4+ helper T cells, while cells positively selected on MHC class I molecules mature into CD8+ cytotoxic T cells. A T cell is then signaled by the thymus to become a CD4+ cell by reducing expression of its CD8 cell surface receptors. If the cell does not lose its signal, it will continue reducing CD8 and become a CD4+, single positive cell. But if there is a signal interruption, it will instead reduce CD4 molecules, eventually becoming a CD8+, single positive cell. This process does not remove thymocytes that may become sensitized against self-antigens, which causes autoimmunity. The potentially autoimmune cells are removed by the process of negative selection.

Negative Selection of T Cells

Negative selection removes thymocytes that are capable of strongly binding with self-antigens presented by MHC. Thymocytes that survive positive selection migrate towards the boundary of the thymic cortex and thymic medulla (the part of the thymus where T cells enter circulation). While in the medulla, they are again presented with self-antigen in complex with MHC molecules on thymic epithelial cells. Thymocytes that interact too strongly with the antigen receive an apoptotic signal that leads to cell death.

However, some cells are selected to become T-reg cells, which retain their ability to bind to self-antigens in order to suppress overactive immune responses. These cells may be protective against autoimmunity. The remaining cells exit the thymus as mature naive T cells. This process is an important component of central tolerance, a process that prevents the formation of self-reactive T cells that are capable of inducing autoimmune diseases in the host. Autoimmune diseases reflect a loss of central tolerance in which the body’s own B and T cells become sensitized towards self-antigens. Many autoimmune disorders are primarily antibody-mediated, but some are T cell mediated. One example of the latter is Crohn’s disease, in which T cells attack the colon. These autoimmune disorders may be caused by problems in negative selection and tend to have genetic components.

Lymphocytes

A lymphocyte is a type of white blood cell in the vertebrate immune system.

A lymphocyte is a type of white blood cell in the immune system, including both the B and T cells of the adaptive immune system and natural killer (NK) cells of the innate immune system.

B and T cells and their various subdivisions perform many adaptive immune functions.

T Cells

T cells mature in the thymus and contain T cell receptors (TCRs) that allow them to bind to antigens on MHC complexes. T cells are a major component in cell-mediated adaptive immunity because they provide a pathway for the direct killing of pathogens. There are two main types of T cells that express either CD4 or CD8 depending on signals that occur during T cell maturation, as well as less common types:

• Helper T cells (CD4s) facilitate the organization of immune responses, and can bind to MHC class II. Subtype 2 helper T cells present antigens to B cells. Subtype 1 helper T cells produce cytokines that guide cytotoxic T cells to pathogens and activate macrophages.
• Cytotoxic T cells (CD8s) destroy pathogens associated with an
  antigen. They function similarly to NK cells by binding to
  MHC class I and releasing perforin, granzymes, and proteases to induce apoptosis in a pathogen. They are different from NK cells because they only bind to
  cells that express their specific antigen, and are not large or granular like NK cells.
• Suppressor T cells (T-reg cells) retain some of their ability to bind to self-cells. They have an immunosuppressive effect that inhibits cell-mediated immunity at the end of a response and destroys autoimmune T cells that aren’t filtered out by negative selection in the thymus.
• Memory T cells are created after an adaptive immune response subsides, retaining the presented antigen. They rapidly proliferate and differentiate into helper and cytotoxic T cells that are specific to that antigen should it be detected in the body again.

While these are the main categories of T lymphocytes, there are other subtypes within these categories as well as additional categories that are not fully understood.

B Cells

B cells are involved in humoral adaptive immunity, producing the antibodies that circulate through the plasma. They are produced and mature in bone marrow tissues and contain B cell receptors (BCRs) that bind to antigens. While in the bone marrow, B cells are sorted through positive and negative selection in a manner somewhat similiar to T cell maturation in the thymus, with the same process of killing B cells that are nonreactive to antigens or reactive to self-antigens. Instead of apoptosis, though, defective B cells are killed through other mechanisms such as clonal deletion. Mature B cells leave the thymus and travel to secondary lymphoid tissue such as the lymph nodes.

During antigen presentation, antigen-presenting cells first present antigens to T cells. Then mature helper T cells bind their antigen to naive B cells through BCRs. After antigen presentation, the naive B cells migrate together to germinal centers within the lymphoid tissue, where they undergo extensive proliferation and differentiation into different types of mature B cells. Some of the major categories of B cells that arise include:

• Plasma cell and long-lived B cells that are the main source of antibodies. They do not have the ability to proliferate and are considered terminally-differentiated.
• Plasmablasts are short-lived B cells produced early in an infection. Their antibodies have a weaker binding affinity than those of plasma cells.
• Regulatory B cells (B reg cells) are immunosuppresive B cells that secrete anti-inflammatory cytokines (such as IL-10) to inhibit autoimmune lymphocytes.
• Memory B cells are dormant B cells with the same BCR as the B cell from which they differentiated. They are specific to the antigen presented to that BCR and rapidly secrete large amounts of antigen-specific antibodies to prevent reinfection if that antigen is detected again.

Besides antibody production, B cells may also function in antigen presentation, though not to the degree of macrophages or dendritic cells. B cells are important to adaptive immune function but can cause problems as well. Autoreactive B cells may cause autoimmune disease that involves antibody-induced damage and inflammation. Certain B cells may undergo malignant tranformation into cancer cells such as lymphoma, in which they continually divide and form solid tumors.

Antigen-Presenting Cells

Antigen presentation is a process by which immune cells capture antigens and then enable their recognition by T cells.

Antigen presentation is a process in the body’s immune system by which macrophages, dendritic cells and other cell types capture antigens, then present them to naive T-cells. The basis of adaptive immunity lies in the capacity of immune cells to distinguish between the body’s own cells and infectious pathogens. The host’s cells express “self” antigens that identify them as belonging to the self. These antigens are different from those in bacteria (“non-self” antigens) or in virally-infected host cells (“missing-self”). Antigen presentation broadly consists of pathogen recognition, phagocytosis of the pathogen or its molecular components, processing of the antigen, and then presentation of the antigen to naive (mature but not yet activated) T cells. The ability of the adaptive immune system to fight off pathogens and end an infection depends on antigen presentation.

Antigen Presenting Cells

Antigen Presenting Cells (APCs) are cells that capture antigens from within the body, and present them to naive T-cells. Many immune system cells can present antigens, but the most common types are macrophages and dendritic cells, which are two types of terminally differentiated leukocytes that arise from monocytes. Both of these APCs perform many immune functions that are important for both innate and adaptive immunity, such as removing leftover pathogens and dead neutrophils after an inflammatory response. Dendritic cells (DCs) are generally found in tissues that have contact with the external environment (such as the skin or respiratory epithelium) while macrophages are found in almost all tissues. Some types of B cells may also present antigens as well, though it is not their primary function.

APCs phagocytize exogenous pathogens such as bacteria, parasites, and toxins in the tissues and then migrate, via chemokine signals, to lymph nodes that contain naive T cells. During migration, APCs undergo a process of maturation in which they digest phagocytized pathogens and begin to express the antigen in the form of a peptide on their MHC complexes, which enables them to present the antigen to naive T cells. The antigen digestion phase is also called “antigen processing,” because it prepares the antigens for presentation. This MHC:antigen complex is then recognized by T cells passing through the lymph node. Exogenous antigens are usually displayed on MHC Class II molecules, which interact with CD4+ helper T cells.

This maturation process is dependent on signaling from other pathogen-associated molecular pattern (PAMP) molecules (such as a toxin or component of a cell membrane from a pathogen) through pattern recognition receptors (PRRs), which are received by Toll-like receptors on the DC’s body. They may also recognize damage-associated molecular pattern (DAMP) molecules, which include degraded proteins or nucleic acids released from cells that undergo necrosis. PAMPs and DAMPS are not technically considered antigens themselves, but instead are signs of pathogen presence that alert APCs through Toll-like receptor binding. However if a DC phagocytzes a PAMP or DAMP, it could be used as an antigen during antigen presentation. APCs are unable to distinguish between different types of antigens themselves, but B and T cells can due to their specificity.

Antigen Presentation

T cells must be presented with antigens in order to perform immune system functions. The T cell receptor is restricted to recognizing antigenic peptides only when bound to appropriate molecules of the MHC complexes on APCs, also known in humans as Human leukocyte antigen (HLA).

Several different types of T cell can be activated by APCs, and each type of T cell is specially equipped to deal with different pathogens, whether the pathogen is bacterial, viral or a toxin. The type of T cell activated, and therefore the type of response generated, depends on which MHC complex the processed antigen-peptide binds to.

MHC Class I molecules present antigen to CD8+ cytotoxic T cells, while MHC class II molecules present antigen to CD4+ helper T cells. With the exception of some cell types (such as erythrocytes), Class I MHC is expressed by almost all host cells. Cytotoxic T cells (also known as TC, killer T cell, or cytotoxic T-lymphocyte (CTL)) are a population of T cells that are specialized for inducing the death of other cells. Recognition of antigenic peptides through Class I by CTLs leads to the killing of the target cell, which is infected by virus, intracytoplasmic bacterium, or are otherwise damaged or dysfunctional. Additionally, some helper T cells will present  their antigen to B cells, which will activate their proliferation response.