Cells of Adaptive Immunity
The principal cells of the adaptive immune system are the lymphocytes, APCs, and effector cells.
Lymphocytes make up approximately 36% of the total white cell count and are the primary cells of the adaptive immune response. They arise from the lymphoid stem cell line in the bone marrow and differentiate into two distinct but inter-related cell types: the B lymphocytes and T lymphocytes. B lymphocytes are responsible for forming the antibodies that provide humoral immunity, whereas T lymphocytes provide cell-mediated immunity. T and B lymphocytes are unique in that they are the only cells in the body capable of recognizing specific antigens present on the surfaces of microbial agents and other pathogens. As a result, adaptive immune processes are organism specific and possess the capacity for memory.
The recognition of specific surface antigens by lymphocytes is made possible because of the presence of specific receptors or antibodies on the surface of B and T lymphocytes. Scientists have been able to identify these specific proteins and correlate them with a specific cellular function. This has lead to the development of a classification system for these surface molecules known as the “cluster of differentiation” (CD). The nomenclature for the surface proteins utilizes the letters “CD” followed by a number that specifies the surface proteins that define a particular cell type or stage of cell differentiation and are recognized by a cluster or group of antibodies. The utilization of this nomenclature has spread to other immune cells and cytokines all of which contribute to the acquired immune response.
Leukocytes involved in the innate immune response, such as macrophages and DCs, also play a key role in adaptive immunity because they function as APCs. They are capable of processing complex antigens into epitopes, which are then displayed on their cell membranes in order to activate the appropriate lymphocytes. Functionally, there are two types of immune cells: regulatory cells and effector cells. The regulatory cells assist in orchestrating and controlling the immune response, while effector cells carry out the elimination of the antigen (microbial, non microbial, or toxin). In the body, helper T lymphocytes activate other lymphocytes and phagocytes, while regulatory T cells keep these cells in check so that an exaggerated immune response does not occur. Cytotoxic T lymphocytes, macrophages, and other leukocytes function as effector cells in different immune responses.
While T and B lymphocytes are generated from lymphoid stem cells in the bone marrow, they do not stay there to mature.
Undifferentiated, immature lymphocytes migrate to lymphoid tissues, where they develop into distinct types of mature lymphocytes (Fig. 13.5). The T lymphocytes first migrate to the thymus gland where they divide rapidly and develop extensive diversity in their ability to react against different antigens. Each T lymphocyte develops specificity against a specific antigen. Once this differentiation occurs, the lymphocytes leave the thymus gland and migrate via the bloodstream to peripheral lymphoid tissue. At this time, they have been preprogrammed not to attack the body’s own issues. Unfortunately, in many autoimmune diseases it is believed that this process goes astray. The B lymphocytes mature primarily in the bone marrow and are essential for humoral, or antibody-mediated, immunity. Unlike the T lymphocytes, where the entire cell is involved in the immune response, B lymphocytes secrete antibodies, which then act as the reactive agent in the immune process. Therefore, the lymphocytes are distinguished by their function and response to antigen, their cell membrane molecules and receptors, their types of secreted proteins, and their tissue location. High concentrations of mature lymphocytes are found in the lymph tissue throughout the body including the lymph nodes, spleen, skin, and mucosal tissues.
T and B lymphocytes possess all of the processes necessary for the adaptive immune response specificity, diversity, memory, and self–nonself recognition. When antigens come in contact with the lymphocytes in the lymphoid tissues of the body, specific T cells become activated and specific B cells are stimulated to produce antibodies. Once the first encounter occurs, these cells can exactly recognize a particular microorganism or foreign molecule because each lymphocyte is capable of targeting a specific antigen and differentiating the invader from self or from other substances that may be similar to it. Cell-mediated and humoral immunity is capable of responding to millions of antigens each day because there is an enormous variety of lymphocytes that have been programmed and selected during cellular development. Once the invading sub- stance or organism has been removed from the body, the lymphocytes “remember” the presenting antigen and can respond rapidly during the next encounter. These lymphocytes are called “memory” T and B lymphocytes. They remain in the body for a longer period of time than their predecessors and as a result can respond more rapidly on repeat exposure. The immune system usually can respond to commonly encountered microorganisms so efficiently that we are unaware of the response.
B and T lymphocyte activation is triggered by antigen presentation to unique surface receptors (Fig. 13.6). The antigen receptor present on the B lymphocyte consists of membrane-bound Ig molecules that can bind a specific epitope. However, in order for B lymphocytes to produce antibodies, they require the help of specific T lymphocytes, called helper T cells. While the B lymphocytes bind to one determinant (or hapten) on an antigen molecule, the antigen-specific helper T cell recognizes and binds to another determinant known as the “carrier.” The carrier is an APC, which has previously picked up the specified antigen. This interaction (B cell–T cell–APC) is restricted by the presence of cellular products genetically encoded by a self-recognition protein, called a major histocom-patibility complex (MHC) molecule. This allows the lymphocyte to differentiate between self and foreign peptides.
Once the B and T lymphocytes are activated and amplified by cytokines released as part of the innate response, the lymphocytes divide several times to form populations or clones of cells that continue to differentiate into several types of effector and memory cells. In the adaptive immune response, the effector cells destroy the antigens and the memory cells retain the ability to target antigen during future encounters.
Major Histocompatibility Complex Molecules
In order for the adaptive immune response to function properly, it must be able to discriminate between molecules that are native to the body and those that are foreign or harmful to the body. The T lymphocytes are designed to respond to a limitless number of antigens, but at the same time they need to be able to ignore self-antigens expressed on tissues. The MHC molecules enable the lymphocytes to do just this. The MHC is a large cluster of genes located on the short arm of chromosome 6. The complex occupies approximately 4 million base pairs and contains 128 different genes, only some of which play a role in the immune response. The MHC genes are divided in three classes: I, II, and III, based upon their underlying function (Fig. 13.7).
The class I and II MHC genes are responsible for encoding human leukocyte antigens (HLAs), which are proteins found on cell surfaces and define the individual’s tissue type. These molecules are present on the cell surface glycoproteins that form the basis for human tissue typing. Each individual has a unique collection of MHC proteins representing a unique set of polymorphisms. MHC polymorphisms affect immune responses as well as susceptibility to a number of diseases. Because of the number of MHC genes and the possibility of several alleles for each gene, it is almost impossible for any two individuals to have an identical MHC profile.
The class I and II MHC genes also encode proteins that play an important role in antigen presentation. Protein fragments from inside the cell are displayed by MHC complex on the cell surface, allowing the immune system to differentiate between the body’s own tissues and foreign substances. Cells, which present unfamiliar peptide fragments on the cell surface, are attacked and destroyed by the B and T lymphocytes. Class III MHC genes encode for many of the components of the complement system and play an important role in the innate immune process.
The MHC-I complexes contain a groove that accommodates a peptide fragment. T-cytotoxic cells can only become activated if they are presented with a foreign antigen peptide. MHC-1 complexes may present degraded viral protein fragments from infected cells. Class II MHC (MHC-II) molecules are found only on phagocytic APCs, immune cells that engulf foreign particles including bacteria and other microbes. This includes the macrophages, DCs, and B lymphocytes, which communicate with the antigen receptor and CD4 molecule on T-helper lymphocytes.
Like class I MHC proteins, class II MHC proteins have a groove or cleft that binds a fragment of antigen. However, these bind fragments from pathogens that have been engulfed and digested during the process of phagocytosis. The engulfed pathogen is degraded into free peptide fragments within cytoplasmic vesicles and then complexed with the MHC-II molecules on the surface of the cells. T-helper cells recognize these complexes on the surface of APCs and become activated.
The first human MHC proteins discovered are called human leukocyte antigens (HLAs) and are so named because they were identified on the surface of white blood cells. HLAs are the major target involved in organ transplant rejection and as a result are the focus of a great deal of research in immunology. Recent analysis of the genes for the HLA molecules has allowed for better understanding of the proteins involved in this response. The classic human MHC-I molecules are divided into types called HLA-A, HLA-B, and HLA-C, and the MHC-II molecules are identified as HLA-DR, HLA-DP, and HLA-DQ (Table 13.3). Multiple alleles or alternative genes can occupy each of the gene loci that encode for HLA molecules. More than 350 possible alleles for the A locus, 650 alleles for the B locus, and 180 alleles for the C locus have been identified. These genes and their expressed MHC molecules are designated by a letter and numbers (i.e., HLA-B27).
HLA genes are inherited as a unit, called a haplotype, because the class I and II MHC genes are closely linked on one chromosome. Since each person inherits one chromosome from each parent, each person has two HLA haplotypes. Tissue typing in forensics and organ transplantation involves the identification of these haplotypes. In organ or tissue transplantation, the closer the matching of HLA types, the greater is the probability of identical antigens and the lower the chance of rejection. However, not all people that develop organ rejection after transplantation develop anti-HLA antibodies. Non-HLA target antigens exist including the MHC class I chain-related antigens A (MICA). These antigens are expressed on epithelial cells, monocytes, fibroblasts, and endothelial cells. Therefore, donor-specific antibodies are not detected prior to organ tissue typing prior to transplantation because they are not expressed on the leukocytes tested.
During the adaptive immune response, activation of a T lymphocyte requires the recognition of a foreign peptide (antigen) bound to a self-MHC molecule. This process requires that stimulatory signals be delivered simultaneously to the T lymphocyte by another specialized cell known as an antigen- presenting cell (APC). Therefore, APCs play a key role in bridging the innate and adaptive immune systems through cytokine-driven up-regulation of MHC-II molecules. Cells that function as APCs must be able to express both classes of MHC molecules and include DCs, monocytes, macrophages, and B lymphocytes residing in lymphoid follicles. Under certain conditions, endothelial cells are also able to function as APCs. APCs have been shown to play a key role in the development of autoimmune diseases and atherosclerosis. Activated T lymphocytes appear to be proatherogenic, and in experimental models, APC and T-cell deficiency have been associated with up to an 80% reduction in atherosclerosis.
Macrophages function as a principal APC. They are key cells of the mononuclear phagocytic system and engulf and digest microbes and other foreign substances that gain access to the body. Since macrophages arise from monocytes in the blood, they can move freely throughout the body to the appropriate site of action. Tissue macrophages are scattered in connective tissue or clustered in organs such as the lung (i.e., alveolar macrophages), liver (i.e., Kupffer cells), spleen, lymph nodes, peritoneum, central nervous system (i.e., microglial cells), and other areas. Macrophages are activated during the innate immune response where they engulf and break down complex antigens into peptide fragments. These fragments can then be associated with MHC-II molecules for presentation to cells of the “cell-mediated” response so that self–nonself recognition and activation of the immune response can occur.
DCs are also responsible for presenting processed antigen to activated T lymphocytes. The starlike structure of the DCs provides an extensive surface area rich in MHC-II molecules and other non-HLA molecules important for initiation of adaptive immunity. DCs are found throughout the body in tissues where antigen enters the body and in the peripheral lymphoid tissues. Both DCs and macrophages are capable of “specialization” depending upon their location in the body. For example, Langerhans cells are specialized DCs in the skin, whereas follicular DCs are found in the lymph nodes. Langerhans cells transport antigens found on the skin to nearby lymph nodes for destruction. They are also involved in the development of cell-mediated immune reactions such as allergic type IV contact dermatitis. Finally, DCs are found in the mucosal lining of the bowel and have been implicated in the development of inflammatory bowel diseases such as Crohn disease and ulcerative colitis, where they present antigens to the B and T lymphocytes through the production of proinflammatory cytokines.