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*In most cases, the ratio of CD4+CD8 to CD8+CD4 is about 2:1. IgG, immunoglobulin G; MHC, major histocompatibility complex.

The total number of lymphocytes in a healthy adult is about 5 x 1011. Of these, ~2% are in the blood, ~10% in the bone marrow, ~15% in the mucosal lymphoid tissues of the gastrointestinal and respiratory tracts, and ~65% in lymphoid organs (mainly the lymph nodes and spleen). We first describe the properties of these cells and then their organization in various lymphoid tissues.

Subsets of Lymphocytes

Lymphocytes consist of distinct subsets that are different in their functions and protein products (Table 2-2). The major classes of lymphocytes were introduced in Chapter 1 (see Fig. 1-5). Morphologically, all lymphocytes are similar, and their appearance does not reflect their heterogeneity or their diverse functions. B lymphocytes, the cells that produce antibodies, were so called because in birds they were found to mature in an organ called the bursa of Fabricius. In mammals, no anatomic equivalent of the bursa exists, and the early stages of B cell maturation occur in the bone marrow. Thus, "B" lymphocytes refer to bursa-derived lymphocytes or bone marrow-derived lymphocytes. T lymphocytes, the mediators of cellular immunity, were named because their precursors, which arise in the bone marrow, migrate to and mature in the thymus; "T" lymphocytes refer to thymus-derived lymphocytes. B and T lymphocytes each consist of subsets with distinct phenotypic and functional characteristics. The major subsets of B cells are follicular B cells, marginal zone B cells, and B-1 B cells, each of which is found in distinct anatomic locations within lym-phoid tissues. The two major T cell subsets are helper CD4+ T lymphocytes and CD8+ CTLs, which express an antigen receptor called the aP receptor. CD4+ regulatory T cells are a third unique subset of T cells expressing the aP receptor. Another population of T cells, called yS T cells, expresses a similar but structurally distinct type of antigen receptor. The different functions of these classes of B and T cells will be discussed in later chapters.

The major populations of B cells and T cells express highly diverse, clonally distributed sets of antigen receptors. Some numerically minor subsets of lymphocytes, including yS T cells, marginal zone B cells, and B-1 B cells, are restricted in their use of DNA segments that contribute to their antigen receptor genes, and these lymphocyte subsets have very limited diversity.

In addition to B and T cells, there exist other populations of cells that are called lymphocytes on the basis of morphology and certain functional and molecular criteria but that are not readily categorized as T or B cells. Natural killer (NK) cells, which are described in Chapter 4, have similar effector functions as CTLs, but their receptors are distinct from B or T cell antigen receptors and are not encoded by somatically recombined genes. NKT cells are a numerically small population of T lymphocytes that are so named because they express a surface molecule typically found on NK cells. They express aP antigen receptors that are encoded by somatically recombined genes, but like y8 T cells and B-1 B cells, they lack diversity. NKT cells, y8 T cells, and B-1 B cells may all be considered part of both adaptive and innate immune systems.

Membrane proteins are used as phenotypic markers to distinguish distinct populations of lymphocytes (see Table 2-2). For instance, most helper T cells express a surface protein called CD4, and most CTLs express a different surface protein called CD8. These and many other surface proteins are often called markers because they identify and discriminate between ("mark") different cell populations. These markers not only delineate the different classes of lymphocytes but also have many functions in the cell types in which they are expressed. The most common way to determine if a surface phenotypic marker is expressed on a cell is to test if antibodies specific for the marker bind to the cell. In this context, the antibodies are used by investigators or clinicians as analytical tools. There are available thousands of different pure antibody preparations, called monoclonal antibodies, each specific for a different molecule and labeled with probes that can be readily detected on cell surfaces by use of appropriate instruments. (Monoclonal antibodies are described in Chapter 5, and methods to detect labeled antibodies bound to cells are discussed in Appendix IV.) The cluster of differentiation (CD) system is a widely adopted uniform method for naming cell surface molecules that are characteristic of a particular cell lineage or differentiation stage, have a defined structure, and are recognized by a group ("cluster") of monoclonal antibodies. Thus, all structurally well defined cell surface molecules are given a CD number designation (e.g., CD1, CD2). A current list of CD markers for leukocytes that are mentioned in the book is provided in Appendix III.

Development of Lymphocytes

After birth, lymphocytes, like all blood cells, arise from stem cells in the bone marrow. The origin of lymphocytes from bone marrow progenitors was first demonstrated by experiments with radiation-induced bone marrow chimeras. Lymphocytes and their precursors are radiosensitive and are killed by high doses of y-irradiation. If a mouse of one inbred strain is irradiated and then injected with bone marrow cells or small numbers of hematopoi-etic stem cells of another strain that can be distinguished from the host, all the lymphocytes that develop subsequently are derived from the bone marrow cells or hematopoietic stem cells of the donor. Such approaches have proved useful for examining the maturation of lymphocytes and other blood cells.

All lymphocytes go through complex maturation stages during which they express antigen receptors and acquire the functional and phenotypic characteristics of mature cells. The anatomic sites where the major steps

Generative lymphoid organs

Blood, lymph

Mature B lymphocytes

Peripheral lymphoid organs

Recirculation

Common lymphoid precursor

Common lymphoid precursor

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