Lymphocytes are responsible for the initial specific recognition of an antigen. Lymphocytes comprise approximately 40% of the total number of white blood cells. They are principally divided into B lymphocytes and T lymphocytes on the basis of their phenotypic expression of cell surface molecules as well as their functional differences. Structurally, B and T cells cannot be distinguished from each other under the microscope, although about 10% to 15% are B cells, and 70% to 80% of circulating blood lymphocytes are T cells; the remainder of lymphocytes are neither B nor T cells, and are often referred to as null cells.
1. Phenotypic identification of B and T lymphocytes is accomplished by immunofluorescence staining using monoclonal antibodies reactive with individual cell surface molecules or antigens. Monoclonal antibodies are produced by antibody-producing hybridoma cell lines, which are capable of forming an antibody that is highly specific and always identical. Fusing a nonsecreting myeloma cell and the antibody-forming cell creates this hybrid cell, which results in an immortalized cell line that produces antibody recognizing a specific antigen. The hybridoma cells can be stored and retrieved to obtain the same antibody whenever needed. The display of many cell surface antigens not only differs by cell type, but also by the particular stage of differentiation and maturation of the cell; thus, the phenotypic expression of these developmentally regulated cell-surface molecules enables distinction between resting and activated cells. Dozens of monoclonal antibodies have been produced that react with cell surface antigens, enabling identification of B- and T-cell subsets and even distinction of cells by their stages of differentiation. Cell surface molecules identified by monoclonal antibodies and subsequently cloned are known as clusters of differentiation (CD) and are numbered sequentially. For example, CD19 is associated with mature B cells, whereas CD3 signifies activated T cells.
2. Lymphocyte subtypes and function. Collectively, the functions of the T and B cells encompass an entity termed the adaptive immune system. B lymphocytes are coated with surface membrane-bound immunoglobulin and a wide variety of other molecules; functionally, B lymphocytes produce antibody. Minor populations of B cells develop in the bone marrow, are polyreactive, and express the CD5 marker, an adhesion and cell surface molecule. These are referred to as B1 cells. The B1 cells express immunoglobulin M (IgM), are polyreactive, and often have a relatively low receptor binding affinity. Other B cells develop lacking the CD5 molecule and are known as B2 cells. Prior to encountering antigen, mature B2 cells coexpress IgM and IgD antibodies on their surface. However, once B2 cells encounter antigen, they usually switch their antigen receptors to IgG, IgA, or IgE. Within secondary lymphoid tissues, complexes of antigen, antibody, and complement are localized in follicular dendritic cells. When these complexes encounter one another, germinal centers are formed, which can be seen on histologic examination as discrete areas in the spleen and lymph nodes. It is within these germinal centers that B2 cells encounter antigen and undergo immunoglobulin class switching via the interaction of CD40 and its ligand, CD40L (also known as CD154). CD40 is a surface marker constitutively expressed on B cells, and CD40L is expressed on an appropriately activated subset of CD4 T cells, known as T helper 2 (Th2) cells. It is the interaction of these two molecules that allows immunoglobulin class switching. It is during immunoglobulin class switching that somatic hypermutation of the antigen receptor genes occurs and high-affinity, antigen-specific IgG, IgA, or IgE are produced. The final stages of B-cell differentiation into antibody-secreting plasma cells continues to occur in secondary lymphoid tissues, but outside the germinal centers. Memory cells and plasma cell precursors are also formed in the germinal centers.
3. T lymphocytes mediate a number of functions, notably the cell-mediated immune responses, such as delayed hypersensitivity, graft rejection, and immune surveillance of neoplastic cells. Quantitative and functional differences distinguish the principal T-cell subsets. CD4 cells predominate over CD8 cells in blood by a ratio of 2:1. CD4 cells provide helper and “inducer” signals for B and T lymphocytes (through various cytokines). CD4 cells also help to mediate CD8 cell cytotoxic actions. In addition, CD4 cells provide inducer signals for macrophages that help to augment the cytotoxic capabilities of macrophages. The CD4 cells are made up of two predominant cell types: Th1 and Th2 cells. These T-cell subsets differentiate from the Th0 cell following antigenic stimulation. A Th1 cell is a helper cell that produces a specific phenotypic profile of cytokines such as interleukin-2 (IL-2) and interferon-g (IFN-g). These cytokines generally inhibit the growth and growth and differentiation of Th2 cells. Th1 cells are primarily involved in cell-mediated immunity, in that they activate macrophages and cytotoxic T cells. A Th2 cell is a helper cell that produces such cytokines as IL-4, 5, 6, 10, and 13. These cells likewise inhibit Th1 responses and are involved primarily in humoral immunity and allergic inflammation. The paradigm of the Th1/Th2 subsets will be discussed in further detail in section III, Immune system functional components. CD8 cells, when influenced by CD4 cells, suppress B lymphocyte immunoglobulin production and T lymphocyte responses to major histocompatibility antigens, and enhance cytotoxicity and natural killing. The CD8+ cells are known as cytotoxic T cells and can function as both suppressor cells and mediate delayed-type hypersensitivity (DTH) reactions. CD8 molecules interact with major histocompatibility complex (MHC) class I molecules. The peptides presented by CD8 cells are derived from endogenous proteins, tumor cells, and viruses found within the antigen presenting cell (APC).
4. Null cells, a part of the innate immune system, include a number of different cell types, including natural killer (NK) cells, which express the markers CD16 and CD56. These cells do not possess the typical appearance of a lymphocyte; they are slightly larger with a kidney-shaped nucleolus and have a granular appearance (large granular lymphocytes [LGL]). NK cells are capable of binding IgG because they have a membrane receptor for the IgG molecule. When a cell is coated with an antibody and destroyed by an NK cell, this phenomenon is called antibody-dependent cell-mediated cytotoxicity (ADCC). Alternatively, NK cells can destroy cells without involvement of antibody (e.g., virally infected cells or tumor cells). Other characteristics of NK cells include recognition of antigens without major histocompatibility restrictions, lack of immunologic memory, and regulation of activity by cytokines and arachidonic acid metabolites.
1. Phenotypic identification of B and T lymphocytes is accomplished by immunofluorescence staining using monoclonal antibodies reactive with individual cell surface molecules or antigens. Monoclonal antibodies are produced by antibody-producing hybridoma cell lines, which are capable of forming an antibody that is highly specific and always identical. Fusing a nonsecreting myeloma cell and the antibody-forming cell creates this hybrid cell, which results in an immortalized cell line that produces antibody recognizing a specific antigen. The hybridoma cells can be stored and retrieved to obtain the same antibody whenever needed. The display of many cell surface antigens not only differs by cell type, but also by the particular stage of differentiation and maturation of the cell; thus, the phenotypic expression of these developmentally regulated cell-surface molecules enables distinction between resting and activated cells. Dozens of monoclonal antibodies have been produced that react with cell surface antigens, enabling identification of B- and T-cell subsets and even distinction of cells by their stages of differentiation. Cell surface molecules identified by monoclonal antibodies and subsequently cloned are known as clusters of differentiation (CD) and are numbered sequentially. For example, CD19 is associated with mature B cells, whereas CD3 signifies activated T cells.
2. Lymphocyte subtypes and function. Collectively, the functions of the T and B cells encompass an entity termed the adaptive immune system. B lymphocytes are coated with surface membrane-bound immunoglobulin and a wide variety of other molecules; functionally, B lymphocytes produce antibody. Minor populations of B cells develop in the bone marrow, are polyreactive, and express the CD5 marker, an adhesion and cell surface molecule. These are referred to as B1 cells. The B1 cells express immunoglobulin M (IgM), are polyreactive, and often have a relatively low receptor binding affinity. Other B cells develop lacking the CD5 molecule and are known as B2 cells. Prior to encountering antigen, mature B2 cells coexpress IgM and IgD antibodies on their surface. However, once B2 cells encounter antigen, they usually switch their antigen receptors to IgG, IgA, or IgE. Within secondary lymphoid tissues, complexes of antigen, antibody, and complement are localized in follicular dendritic cells. When these complexes encounter one another, germinal centers are formed, which can be seen on histologic examination as discrete areas in the spleen and lymph nodes. It is within these germinal centers that B2 cells encounter antigen and undergo immunoglobulin class switching via the interaction of CD40 and its ligand, CD40L (also known as CD154). CD40 is a surface marker constitutively expressed on B cells, and CD40L is expressed on an appropriately activated subset of CD4 T cells, known as T helper 2 (Th2) cells. It is the interaction of these two molecules that allows immunoglobulin class switching. It is during immunoglobulin class switching that somatic hypermutation of the antigen receptor genes occurs and high-affinity, antigen-specific IgG, IgA, or IgE are produced. The final stages of B-cell differentiation into antibody-secreting plasma cells continues to occur in secondary lymphoid tissues, but outside the germinal centers. Memory cells and plasma cell precursors are also formed in the germinal centers.
3. T lymphocytes mediate a number of functions, notably the cell-mediated immune responses, such as delayed hypersensitivity, graft rejection, and immune surveillance of neoplastic cells. Quantitative and functional differences distinguish the principal T-cell subsets. CD4 cells predominate over CD8 cells in blood by a ratio of 2:1. CD4 cells provide helper and “inducer” signals for B and T lymphocytes (through various cytokines). CD4 cells also help to mediate CD8 cell cytotoxic actions. In addition, CD4 cells provide inducer signals for macrophages that help to augment the cytotoxic capabilities of macrophages. The CD4 cells are made up of two predominant cell types: Th1 and Th2 cells. These T-cell subsets differentiate from the Th0 cell following antigenic stimulation. A Th1 cell is a helper cell that produces a specific phenotypic profile of cytokines such as interleukin-2 (IL-2) and interferon-g (IFN-g). These cytokines generally inhibit the growth and growth and differentiation of Th2 cells. Th1 cells are primarily involved in cell-mediated immunity, in that they activate macrophages and cytotoxic T cells. A Th2 cell is a helper cell that produces such cytokines as IL-4, 5, 6, 10, and 13. These cells likewise inhibit Th1 responses and are involved primarily in humoral immunity and allergic inflammation. The paradigm of the Th1/Th2 subsets will be discussed in further detail in section III, Immune system functional components. CD8 cells, when influenced by CD4 cells, suppress B lymphocyte immunoglobulin production and T lymphocyte responses to major histocompatibility antigens, and enhance cytotoxicity and natural killing. The CD8+ cells are known as cytotoxic T cells and can function as both suppressor cells and mediate delayed-type hypersensitivity (DTH) reactions. CD8 molecules interact with major histocompatibility complex (MHC) class I molecules. The peptides presented by CD8 cells are derived from endogenous proteins, tumor cells, and viruses found within the antigen presenting cell (APC).
4. Null cells, a part of the innate immune system, include a number of different cell types, including natural killer (NK) cells, which express the markers CD16 and CD56. These cells do not possess the typical appearance of a lymphocyte; they are slightly larger with a kidney-shaped nucleolus and have a granular appearance (large granular lymphocytes [LGL]). NK cells are capable of binding IgG because they have a membrane receptor for the IgG molecule. When a cell is coated with an antibody and destroyed by an NK cell, this phenomenon is called antibody-dependent cell-mediated cytotoxicity (ADCC). Alternatively, NK cells can destroy cells without involvement of antibody (e.g., virally infected cells or tumor cells). Other characteristics of NK cells include recognition of antigens without major histocompatibility restrictions, lack of immunologic memory, and regulation of activity by cytokines and arachidonic acid metabolites.
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