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Lymphocytes


Lymphocytes
As befits the cell of adaptive immunity, the lymphocyte has several unique features: restricted receptors permitting each cell to respond to an individual antigen (the basis of specificity), clonal proliferation and long lifespan (the basis of memory), and recirculation from the tissues back into the bloodstream, which ensures that specific memory following a local response has a body-wide distribution.

Lymphocytes, Naïve cells, Memory cells, Polyclonal activation, Helper T cell, Regulatory T cell

The discovery in the early 1960s of the two major lymphocyte sub-populations, T (thymus-dependent; top) and B (bursa or bone marrow- dependent;   bottom),   had   roughly   the   same   impact   on   cellular immunology as the double helix on molecular biology. The first property of T cells to be distinguished was that of ‘helping’ B cells to make antibody, but further subdivisions have subsequently come to light, based on both functional and physical differences (top right). In the figure, the main surface features (or ‘markers’) of the various stages of lymphocyte differentiation are given, using mainly the CD classification (see Appendix III) but also indicating the production of key cytokines. Cells resembling lymphocytes, but without characteristic T-cell or
B-cell markers, are referred to as ‘null’. This group probably includes early T cells, B cells and ‘natural killer’ cells important in tumour and virus immunity. In blood and lymphoid organs, up to 10% of lymphocytes are ‘null’.
One of the most exciting developments in biology was the discovery that it is possible to perpetuate individual lymphocytes by fusing them with a tumour cell. In the case of B lymphocytes, this can mean an endless supply of individual, or monoclonal, antibodies, which has had far-reaching applications in the diagnosis and treatment of disease and the study of cell surfaces. Indeed, the classification of lymphocytes themselves, and of most other cells too, is now mainly based on pat- terns of reactivity with a large range of monoclonal typing antibodies (see Appendix III).
In the case of T cells, it is also possible to keep them proliferating indefinitely  in  culture  by  judicious  application  of  their specific antigen and non-specific growth factors such as IL-2 (see Figs 23 and 24). The properties of the  resulting  lines  or  clones have  given  much  information  on  the  regulation  of  normal  T-cell function.
Naïve cells  Once mature, lymphocytes (B or T) circulate through blood and lymph nodes in search of specific antigen. These cells can be very long-lived, and divide only very rarely. Such lymphocytes, which have yet to encounter antigen, are known as naïve or virgin (see Fig. 17). Naïve T cells enter lymph nodes from blood at special sites known as high endothelial venules (HEV). They then travel though the lymph node in search of antigen presented on the surface of antigen- presenting dendritic cells in the T-cell areas of lymphoid tissues.
Memory cells After lymphocytes encounter antigen they enter cell division, in order to increase the number of cells specific for that particular antigen. A proportion of cells then become memory cells. The migratory paths of memory cells and naïve cells are quite distinct; memory cells leave blood vessels at the site of an infection, enter tissues and then travel back to lymph nodes via the lymphatics. Memory cells can persist for many years, dividing every few months, even in the absence of further antigen stimulation. Most memory T cells are conveniently distinguished from naïve T cells by expression of the CD45RO and CD45RA surface markers, respectively.
Effector cells After  they  encounter  antigen, a  proportion  of  lymphocytes differentiate into effector cells, expressing molecules required to perform their ultimate function in defending the body against disease. B-cell effectors mostly settle in the bone marrow, where they produce antibody, and are known as plasma cells. T cells can become helper cells (TH), cytotoxic cells (CTLs, TC) or regulatory cells (TREG). Effector T cells migrate to the site of infection, and usually stop recirculating or dividing further.
NK Natural killer cells are cytotoxic to some virus-infected cells and some tumours (see also Fig. 42). NK cells express a special class of polymorphic killer inhibitory receptors (KIRs) which bind self- MHC and then negatively signal to the cell to prevent activation of cytotoxicity. NK cells are therefore only activated when cells lose expression of MHC molecules, such as sometimes occurs during viral infection or tumour growth. They thus form an important counterpart to cytotoxic T cells (see below), which kill cells only when they do express MHC molecules. An intermediate cell type known as the NK-T cell uses a restricted set of T-cell receptors to respond to bacterial glycolipids presented by CD1 molecules, but has many of the properties of NK cells.
T cells The subset of lymphocytes that develop within the thymus (see Fig. 16). All T cells express one form of the TCR with which they recognize antigen.
Two alternative types of TCR exist, consisting either of a dimer made up of an α and a β chain or, a γδ dimer (see Fig. 12).
CD A classification of the molecules found on the surface of haemopoietic cells based on reaction with panels of monoclonal antibodies. The profile of CD antigens expressed by cells is used to classify them. A list of CD numbers is given in Appendix III, but it should be noted that some older functional names (C3 receptor, Fc receptor, etc.) are still in use.
Polyclonal activation Stimulation of many clones, rather than the few or single clones normally stimulated by an antigen. Because the first sign of activation is often mitosis, polyclonal activators are sometimes known as ‘mitogens’. Several T-cell polyclonal activators are of plant origin, e.g. concanavalin A (CON A) and phytohaemagglutinin (PHA). Dextran sulphate, lipopolysaccharide (e.g. Salmonella endotoxin) and Staphylococcus aureus cell wall are normally mitogenic only for B cells. They have provided a useful tool for the study of lymphocyte activation.
Cytotoxic T cell (TC) Cytotoxic T cells kill cells expressing their specific antigen target. The killing is triggered by binding of the TCR to MHC bound to appropriate antigen peptide fragments (see Fig. 18). The target cell is killed either by the release of perforin and granzymes, or by expression of CD154 (also known as Fas ligand) on the T-cell surface that engages CD95 (Fas) on the target. In both cases, the target cell dies by programmed cell death (also known as apoptosis). CTLs are key cells in virus immunity (see Figs 27 and 28) and immune responses to tumours (Fig. 42). Prolonged stimulation of cytotoxic T cells, e.g. due to chronic infection or cancer, can lead to cell exhaus- tion, in which large numbers of T cells persist but have greatly impaired cytotoxic activity and cytokine production.

Helper T cell (TH) The CD4 T cell is essential for most antibody and cell-mediated responses (see Figs 18, 19 and 21). CD4 T cells can be further subdivided on the basis of which cytokines they secrete. TH1 cells, for example, make cytokines such as IFNγ and TNF-α important for activating macrophages or delayed hypersensitivity. In contrast, TH2 cells make cytokines needed for helping B cells to make certain types of antibody, especially IgE. The most recent T-helper subtype to be defined are confusingly named TH17 because they secrete the cytokine IL-17. These cells are important in recruiting neutrophils, and especially in protection against fungal infection (see Fig. 30), but they are also frequently associated with autoimmunity (see Fig. 38).
Regulatory T cell (TREG)  These cells are the major regulators of the immune response. They can be distinguished from other T cells by the expression of high levels of CD25 and the transcription factor FOXP3. “Natural” TREG come directly from the thymus, and help maintain self- tolerance (Fig. 22). Other types of TREG can be induced during infection and work by the release of inhibitory cytokines such as IL-10 and TGF-β.
B cells Lymphocytes whose antigen-specific receptor is antibody (Ig, see Figs 13 and 14). B cells develop in the bone marrow (or liver in the fetus) where they pass through various stages (pre-B and pro-B cells) that are required for the full assembly of the antibody molecule (see Fig. 13). Many cells die during this developmental process due to incorrect antibody assembly or because they recognize self-antigen B cells produce.
Plasma cells are non-motile and are found predominantly in bone marrow or spleen. Their cytoplasm is completely filled with an enormously enlarged rough endoplasmic reticulum devoted to synthesis and secretion of soluble antibody. Most plasma cells are short-lived (1–2 weeks) but some may survive much longer. Some antibody formation, especially IgM, does not require T-cell help, and is called ‘thymus independent’. It usually involves direct cross-linking of anti- body on the B-cell surface by multivalent antigens such as bacterial cell wall polysaccharides. T-independent responses tend to be short- lived and show very weak memory.
PCD Programmed cell death, also known as apoptosis; a process by which cells are induced to die without damage to surrounding tissue. A very high proportion of both B and T cells die in this way because they fail to rearrange their receptor genes properly, or because they threaten to be ‘self-reactive’ (see Fig. 38). Mutations in CD95, a key receptor activating PCD in lymphocytes, are associated with a multi-organ autoimmune disease, illustrating the importance of this pathway in regulating the normal immune response.