Naive lymphocytes that have matured in the bone marrow or thymus migrate into secondary (peripheral) lymphoid organs, where they are activated by antigens to proliferate and differentiate into effector and memory cells (Fig. 1 and Table 1). The mature T cells that emerge from the thymus are called naive T lymphocytes. B cells undergo most of their development in the bone marrow, but the final steps that generate mature naïve B lymphocytes occur in the spleen. Naive lymphocytes are functionally quiescent, but after activation by an antigen, they proliferate and go through dramatic changes in phenotype and functional activity. The activation of naive lymphocytes follows a series of sequential steps beginning with the synthesis of new proteins, such as cytokine receptors and cytokines, which are required for many of the subsequent changes. The cells then undergo proliferation, resulting in clonal expansion. In some infections, the number of microbe-specific T cells may increase more than 50,000-fold within a week, and the number of specific B cells may increase up to 5000-fold. This rapid clonal expansion of microbe-specific lymphocytes is needed to keep pace with the ability of microbes to rapidly replicate. Concurrently with proliferation, antigen-stimulated lymphocytes begin to differentiate into effector cells, whose function is to eliminate the antigen. Many of the effector cells migrate into tissue sites of infection, and some stay in secondary lymphoid organs. Other progeny of antigen-stimulated B and T lymphocytes differentiate into long-lived memory cells, whose function is to mediate rapid and enhanced (i.e., secondary) responses to subsequent exposures to antigens. Naive, effector, and memory lymphocytes can be distinguished by several functional and phenotypic criteria (see Table 1).

Fig1. Stages in the life history of lymphocytes. In response to an antigen, naive lymphocytes in secondary lymphoid proliferate and differentiate into effector cells, which function to eliminate antigens. The effector cells of the B-lymphocyte lineage are antibody-secreting plasma cells (some of which are long lived). The effector cells of the CD4 T-lymphocyte lineage are cytokine-producing helper T cells, and the effector cells of the CD8 lineage (not shown) are cytotoxic T lymphocytes (CTLs). Most effector T cells leave secondary lymphoid organs and migrate into infected tissues. Some helper T cells remain in the secondary lymphoid organs, where they help B cells mount antibody responses. Other progeny of the antigen-stimulated lymphocytes differentiate into long-lived memory cells, which are located in secondary lymphoid organs and nonlymphoid tissues. See Table 1 for features of naive, effector, and memory lymphocytes.

Table1. Characteristics of Naive, Effector, and Memory Lymphocytes

The details of lymphocyte activation and differentiation, as well as the functions of each of these populations, will be addressed later in the book. Here we will summarize the phenotypic characteristics of each population.

Naive Lymphocytes. Naive (immunologically inexperienced) lymphocytes are mature T or B cells that have never encountered foreign antigen. Naive lymphocytes are found in the circulation and secondary lymphoid organs. Naive and memory lymphocytes are both called resting lymphocytes because they are not actively dividing or performing effector functions and are in a state of rest, or in the G0 stage of the cell cycle, before antigenic stimulation. Naive (and memory) B and T lymphocytes cannot be readily distinguished morpho logically, and both are often called small lymphocytes when observed in blood smears. A small lymphocyte is 8 to 10 μm in diameter and has a large nucleus with dense heterochromatin and a thin rim of cytoplasm that contains a few mitochondria, ribosomes, and lysosomes but no visible specialized organelles (Fig. 2). Naive (and memory) lymphocytes rely mainly on oxidative phosphorylation and fatty acid oxidation to maintain their basal energy requirements.

Fig2. Morphology of lymphocytes. (A) Light micrograph of a lymphocyte in a peripheral blood smear. (B) Electron micrograph of a small lymphocyte. (C) Light micrograph of a large lymphocyte (lymphoblast). (D) Electron micrograph of a large lymphocyte (lymphoblast). A and C, Courtesy Jean Shafer, Department of Pathology, University of California, San Diego. Copyright 1995–2008, Carden Jennings Publishing Co., Ltd. B, Courtesy Dr. Noel Weidner, Department of Pathology, University of California, San Diego. D, From Fawcett DW. Bloom and Fawcett: A Textbook of Histology. 12th ed. Chapman & Hall; 1994.

Naive lymphocytes typically live for 1 to 3 months. Their survival requires signals from antigen receptors and cytokines. The need for antigen receptor expression to maintain the pool of naive lymphocytes in secondary lymphoid organs was demonstrated in studies with mice in which the genes that encode the antigen receptors of B cells or T cells were deleted after the lymphocytes had matured. In these studies, naive lymphocytes that lost their antigen receptors died within 2 or 3 weeks. It has been shown that the antigen receptor of naive B cells generates survival signals even in the absence of antigen. Naive T lymphocytes recognize various self antigens weakly, enough to induce survival signals but without triggering the stronger signals that are needed to initiate proliferation and differentiation into effector cells.

Cytokines are also essential for the survival of naive lymphocytes, and naive B and T cells express receptors for these cytokines. The most important of these cytokines are IL-7, which promote survival and low-level cycling of naive T cells, and B cell–activating factor (BAFF), which is required for naive B-cell survival.

In the steady state, or homeostasis, the pool of naive lymphocytes is maintained at a fairly constant number because of a balance between spontaneous death of these cells and the production of new cells in the primary lymphoid organs. Any loss of lymphocytes leads to compensatory proliferation of the remaining ones and increased output from the primary organs. This response of the immune system to reestablish a normal total number of lymphocytes is called homeostatic proliferation. If naive cells are transferred into a host that is deficient in lymphocytes (said to be lymphopenic), the transferred lymphocytes begin to proliferate and increase in number until they reach approximately the numbers of lymphocytes in normal animals. Homeostatic proliferation appears to be driven by the same signals that are required for the maintenance of naive lymphocytes, namely weak recognition of some self antigens in the case of T cells or spontaneous B-cell receptor signaling in B cells, and cytokines, mainly IL-7. This phenomenon is exploited clinically in T-cell therapy protocols, as in the treatment of some leukemias—the transferred T cells proliferate maximally if host T-cell numbers are reduced, a process called lymphodepletion.

Effector Lymphocytes. In response to stimulation by anti gens and other signals, naive lymphocytes enter the G1 stage of the cell cycle before going on to divide. Activated lymphocytes are larger (10–12 μm in diameter), have more cytoplasm and organelles and increased amounts of cytoplasmic RNA, and are called large lymphocytes or lymphoblasts (see Fig. 2). These changes require more energy and substrates for biosynthetic activities. The recently activated lymphocytes use aerobic glycolysis for energy and the tricarboxylic acid cycle to generate the intermediary metabolites needed for new synthesis of proteins, lipids, and nucleic acids.

Some of these activated lymphocytes differentiate into effector lymphocytes that have the ability to produce molecules capable of eliminating foreign antigens. Effector T lymphocytes include CD4+ helper T cells and CD8+ CTLs, and effector B lymphocytes are antibody-secreting cells, mainly plasma blasts and plasma cells. By convention, the term effector cells is usually only used for T cells and the effector cells in the B-cell lineage are plasma cells. Helper T cells activate B lymphocytes, macrophages, and DCs by secreting cytokines that bind to receptors on these cells and surface molecules, such as CD40 ligand (CD154), which engages CD40 on other cells. CTLs have cytoplasmic granules filled with proteins that, when released, kill the cells that the CTLs recognize, which are usually virus-infected cells or tumor cells. Both CD4+ and CD8+ effector T cells may transiently express surface proteins indicative of recent activation, including CD25 (a component of the receptor for the T-cell growth factor IL-2), and altered patterns of molecules that mediate migration (selectins, integrins, and chemokine receptors). The majority of differentiated effector T lymphocytes migrate from secondary lymphoid organs, where they were generated, into tissue sites of infections and are short lived.

Many antibody-secreting B cells are morphologically identifiable in stained tissue sections as plasma cells. They have characteristic nuclei placed eccentrically in the cell with the chromatin distributed around the nuclear membrane in a cartwheel pat tern; abundant cytoplasm containing dense, rough endoplasmic reticulum that is the site where antibodies (and other secreted and membrane proteins) are synthesized; and distinct peri nuclear Golgi complexes, where antibody molecules are post translationally modified to their final forms and packaged for secretion (Fig. 3). It is estimated that half or more of the messenger RNA in these cells codes for antibody proteins and a single plasma cell can secrete thousands of antibody molecules per second. Plasma cells develop in lymphoid organs and at sites of infection, and some of them migrate to the bone marrow or mucosal tissues, where they may live and secrete antibodies for long periods after the immune response is induced and even after the antigen is eliminated. Plasma cells do not proliferate and, because their antibodies are secreted but not membrane-bound, they do not express antigen receptors and cannot respond to antigens. Also, they are not present in the blood. Plasmablasts are antibody-secreting cells with features of plasma cells but that are capable of proliferation; they are found in the circulation and can be identified by the expression of CD19 and lower levels of the typical B-cell marker CD20 than naive and memory B cells. Within a week after an infection, a large number of plasmablasts can be detected in the blood. These cells secrete IgM, IgG, or IgA antibodies and are derived from naive or memory B cells that were recently activated in secondary lymphoid organs. Some of these circulating plasmablasts may be in transit from the lymphoid organs where they were generated to the bone marrow and mucosal tissues, where they will remain as long-lived plasma cells.

Fig3. Morphology of plasma cells. (A) Light micrograph of a plasma cell in tissue. (B) Electron micrograph of a plasma cell. Courtesy Dr. Noel Weidner, Department of Pathology, University of California, San Diego.

Memory Lymphocytes. Memory cells are produced during infections and may survive in a functionally quiescent or slowly cycling state for months or years after the microbe is eliminated. Some memory cells recirculate between blood and lymphoid tissues, similar to naive T cells, and others remain within non lymphoid tissues without reentering the blood for long periods. Memory lymphocytes can be identified by their expression of surface proteins that distinguish them from naive and recently activated effector lymphocytes, although it is still not clear which of these surface proteins are definitive markers of memory populations (see Table1). Memory T cells, like naive but not effector T cells, express high levels of the IL-7 receptor. Memory T cells also express molecules that regulate their migration into and out of lymphoid organs or tissue sites of infection. In humans, most naive T cells express an isoform of the cell surface protein CD45 called CD45RA. In contrast, most activated and memory T cells express a different isoform called CD45RO. However, this way of distinguishing naive from memory T cells is not perfect, and interconversion between CD45RA+ and CD45RO+ populations has been documented.

The frequency of memory cells increases with age because individuals are continually exposed to foreign antigens, such as environmental microbes, which induce memory cell generation. Memory T cells make up less than 5% of peripheral blood T cells in a newborn but 50% or more in an adult (Fig. 4). As individuals age, the gradual accumulation of memory cells compensates for the reduced output of new naive T cells from the thymus, which involutes after puberty.

Fig4. Change in proportions of naive and memory T cells with age. The proportions of naive and memory T cells are based on data from multiple healthy individuals. The estimate of thymic output is an approximation. Courtesy Dr. Donna L. Farber, Columbia University College of Physicians and Surgeons, New York.

Memory B lymphocytes may express certain classes (isotypes) of membrane Ig, such as IgG, IgE, or IgA, as a result of class switching, whereas naive B cells express only IgM and IgD. In humans, CD27 expression is a marker for memory B cells.

Memory cells are heterogeneous and consist of subsets that differ in their location and migratory properties.

The distinguishing features of naive, effector, and memory lymphocytes reflect different programs of gene expression that are regulated by transcription factors and stable epigenetic changes, including histone methylation and acetylation and chromatin remodeling. For example, a transcription factor called Kruppel-like factor 2 (KLF2) is required for maintenance of the naive T-cell phenotype. The phenotypes of functionally different types of CD4+ effector T cells, called Th1, Th2, and Th17 cells, depend on transcription factors T-BET, GATA3, and RORγT, respectively, as well as epigenetic changes in cytokine gene loci. Other transcription factors are required for maintaining the phenotypes of memory B and T cells. Our understanding of the molecular determinants of lymphocyte phenotype is still evolving.

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