The adaptive, or acquired, immune response takes days or even weeks to become established – much longer than the innate response; however, adaptive immunity is more specific to an invading pathogen. Adaptive immunity is an immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. An antigen is a molecule that stimulates a response in the immune system. This part of the immune system is activated when the innate immune response is insufficient to control an infection. In fact, without information from the innate immune system, the adaptive response could not be mobilized.
There are two types of adaptive responses: the cell-mediated immune response, which is controlled by activated T cells, and the humoral immune response, which is controlled by activated B cells and antibodies. Activated T and B cells whose surface binding sites are specific to the molecules on the pathogen greatly increase in numbers and attack the invading pathogen. Their attack can kill pathogens directly or they can secrete antibodies that enhance the phagocytosis of pathogens and disrupt the infection. Adaptive immunity also involves a memory to give the host long-term protection from reinfection with the same type of pathogen; on re-exposure, this host memory will facilitate a rapid and powerful response.
B and T Cells
Lymphocytes are a class of leukocytes that are formed with other blood cells in the red bone marrow found in many flat bones, such as the shoulder or pelvic bones. Lymphocytes have the following properties that differentiate them from other cells of the immune system: are mobile cells, do not have the ability to phagocytose like macrophages, adhere easily to other cells, have membrane receptors and, under the influence of certain mitogenic substances, can transform blast.
The two types of lymphocytes of the adaptive immune response are B and T cells (Figure 12.1). Whether an immature lymphocyte becomes a B cell or T cell depends on where in the body it matures. The B cells remain in the bone marrow to mature (hence the name “B” for “bone marrow”), while T cells migrate to the thymus, where they mature (hence the name “T” for “thymus”).
Maturation of a B or T cell involves becoming immuno-competent, meaning that it can recognize, by binding, a specific molecule or antigen. During the maturation process, B and T cells that bind too strongly to the body’s own cells are eliminated in order to minimize an immune response against the body’s own tissues. Those cells that react weakly to the body’s own cells, but have highly specific receptors on their cell surfaces that allow them to recognize a foreign molecule or antigen remain. This process occurs during fetal development and continues throughout life. The specificity of this receptor is determined by the genetics of the individual and is present before a foreign molecule is introduced to the body or encountered. Thus, it is genetics and not experience that initially provides a vast array of cells, each capable of binding to a different specific foreign molecule. Once they are immuno-competent, the T and B cells will migrate to the spleen and lymph nodes, where they will remain until they are called on during an infection.
B cells are involved in the humoral immune response, which targets pathogens loose in blood and lymph. T cells are involved in the cell-mediated immune response, which targets infected cells.
Figure 12.1: This scanning electron micrograph shows a T lymphocyte. T and B cells are indistinguishable by light microscopy but can be differentiated experimentally by probing their surface receptors (credit: modification of work by NCI; scale-bar data from Matt Russell).
Humoral Immune Response
An antigen is a molecule that stimulates a response in the immune system. Not every molecule is antigenic. B cells participate in a chemical response to antigens present in the body by producing specific antibodies that circulate throughout the body and bind with the antigen whenever it is encountered. This is known as the humoral immune response. During maturation of B cells, a set of highly specific B cells are produced that have many antigen receptors in their membrane (Figure 12.2).
Figure 12.2: B cell receptors are embedded in the membranes of B cells and bind a variety of antigens through their variable regions.
Each B cell has only one kind of antigen receptors, which makes every B cell different. Once the B cells mature in the bone marrow, they migrate to lymph nodes or other lymphatic organs. When a B cell encounters the antigen that binds to its receptor, the antigen molecule is brought into the cell by endocytosis and reappears on the surface of the cell bound to an MHC II molecule. When this process is complete, the B cell is sensitized. In most cases, the sensitized B cell must then encounter a specific kind of T cell, called a helper T cell, before it is activated. The helper T cell must already have been activated through an encounter with the antigen. The helper T cell binds to the antigen-MHC II complex and is induced to release cytokines that induce the B cell to divide rapidly, which makes thousands of identical (clonal) cells.
These daughter cells become either plasma cells or memory B cells. The memory B cells remain inactive at this point, until another later encounter with the antigen, caused by a reinfection by the same bacteria or virus, results in them dividing into a new population of plasma cells. The plasma cells, on the other hand, produce and secrete large quantities, up to 100 million molecules per hour, of antibody molecules.
An antibody, also known as an immunoglobulin (Ig), is a large, Y-shaped protein that is produced by plasma cells after stimulation by an antigen. In mammals there are five types of antibodies: IgA, IgD, IgE, IgG, IgM, having different properties. Antibodies are the agents of humoral immunity. Antibodies occur in the blood, in gastric and mucus secretions, and in breast milk. Antibodies in these bodily fluids can bind pathogens and mark them for destruction by phagocytes before they can infect cells. These antibodies circulate in the blood stream and lymphatic system and bind with the antigen whenever it is encountered.
The binding can fight infection in several ways. Antibodies can bind to viruses or bacteria and interfere with the chemical interactions required for them to infect or bind to other cells. The antibodies may create bridges between different particles containing antigenic sites clumping them all together and preventing their proper functioning. The antigen-antibody complex stimulates the complement system destroying the cell bearing the antigen. Phagocytic cells, such as those already described, are attracted by the antigen-antibody complexes, and phagocytosis is enhanced when the complexes are present. Finally, antibodies stimulate inflammation, and their presence in mucus and on the skin prevents pathogen attack.
Antibodies coat extracellular pathogens and neutralize them by blocking key sites on the pathogen that enhance their infectivity (such as receptors that “dock” pathogens on host cells) (Figure 12.3). Antibody neutralization can prevent pathogens from entering and infecting host cells. The neutralized antibody-coated pathogens can then be filtered by the spleen and eliminated in urine or feces. Antibodies also mark pathogens for destruction by phagocytic cells, such as macrophages or neutrophils, in a process called opsonization. In a process called complement fixation, some antibodies provide a place for complement proteins to bind.
The combination of antibodies and complement promotes rapid clearing of pathogens. The production of antibodies by plasma cells in response to an antigen is called active immunity and describes the hosts’ active response of the immune system to an infection or to a vaccination. There is also a passive immune response where antibodies come from an outside source, instead of the individual’s own plasma cells, and are introduced into the host. For example, antibodies circulating in a pregnant woman’s body move across the placenta into the developing fetus. The child benefits from the presence of these antibodies for up to several months after birth. In addition, a passive immune response is possible by injecting antibodies into an individual in the form of an antivenom to a snake-bite toxin or antibodies in blood serum to help fight a hepatitis infection. This gives immediate protection since the body does not need the time required to mount its own response.
Figure 12.3: Antibodies may inhibit infection by (a) preventing the antigen from binding its target, (b) tagging a pathogen for destruction by macrophages or neutrophils, or (c) activating the complement cascade.
Cell-Mediated Immunity
Unlike B cells, T lymphocytes are unable to recognize pathogens without assistance. Instead, dendritic cells and macrophages first engulf and digest pathogens into hundreds or thousands of antigens. Then, an antigen presenting cell (APC) detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will engulf and break it down through phagocytosis. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells.
A dendritic cell is an immune cell that mops up antigenic materials in its surroundings and presents them on its surface. Dendritic cells are located in the skin, the linings of the nose, lungs, stomach, and intestines. These positions are ideal locations to encounter invading pathogens. Once they are activated by pathogens and mature to become APCs they migrate to the spleen or a lymph node.
Macrophages also function as APCs. After phagocytosis by a macrophage, the phagocytic vesicle fuses with an intracellular lysosome. Within the resulting phagolysosome, the components are broken down into fragments; the fragments are then loaded onto MHC II molecules and are transported to the cell surface for antigen presentation (Figure 12.4). Helper T cells cannot properly respond to an antigen unless it is processed and embedded in an MHC II molecule. The APCs express MHC II on their surfaces, and when combined with a foreign antigen, these complexes signal an invader.
Figure 12.4: An antigen-presenting cell (APC) such as a macrophage engulfs a foreign antigen, partially digests it in a lysosome, and then embeds it in an MHC II molecule for presentation at the cell surface. Lymphocytes of the adaptive immune response must interact with antigen-embedded MHC II molecules to mature into functional immune cells.
T cells have many functions. Some respond to APCs of the innate immune system and indirectly induce immune responses by releasing cytokines. Others stimulate B cells to start the humoral response as described previously. Another type of T cell detects APC signals and directly kills the infected cells, while some are involved in suppressing inappropriate immune reactions to harmless or “self” antigens. There are two main types of T cells: the helper T lymphocytes (TH) and the cytotoxic T lymphocytes (TC).
The helper T lymphocytes (TH) function indirectly to tell other immune cells about potential pathogens. TH lymphocytes recognize specific antigens presented by the MHC II complexes of APCs. There are two populations of TH cells: TH1 and TH2. TH1 cells secrete cytokines to enhance the activities of macrophages and other T cells. TH2 cells stimulate naive B cells to secrete antibodies. Whether a TH1 or a TH2 immune response develops depends on the specific types of cytokines secreted by cells of the innate immune system, which in turn depends on the nature of the invading pathogen.
The cytotoxic T lymphocytes (TC) are the key component of the cell-mediated part of the adaptive immune system and attack and destroy infected cells. TC cells are particularly important in protecting against viral infections; this is because viruses replicate within cells where they are shielded from extracellular contact with circulating antibodies. Once activated, the TC creates a large clone of cells with one specific set of cell-surface receptors, as in the case with proliferation of activated B cells. As with B cells, the clone includes active TC cells and inactive memory TC cells. The resulting active TC cells then identify infected host cells. Because of the time required to generate a population of clonal T and B cells, there is a delay in the adaptive immune response compared to the innate immune response. TC cells attempt to identify and destroy infected cells before the pathogen can replicate and escape, thereby halting the progression of intracellular infections. TC cells also support NK lymphocytes to destroy early cancers. Cytokines secreted by the TH1 response that stimulates macrophages also stimulate TC cells and enhance their ability to identify and destroy infected cells and tumors.
A summary of how the humoral and cell-mediated immune responses are activated appears in Figure 12.5. B plasma cells and TC cells are collectively called effector cells because they are involved in “effecting” (bringing about) the immune response of killing pathogens and infected host cells.
Figure 12.5: A helper T cell becomes activated by binding to an antigen presented by an APC via the MHC II receptor, causing it to release cytokines. Depending on the cytokines released, this activates either the humoral or the cell mediated immune response.
References:
- Fowler, Samantha, et al. Concepts of Biology. OpenStax College, Rice University, 2013. Download for free at: https://openstax.org/details/books/concepts-biology.