The great majority of cells involved in mammalian immunity are derived from precursors in the bone marrow (left half of figure 1) and circulate in the blood, entering and sometimes leaving the tissues when required. A very rare stem cell persists in the adult bone marrow (at a frequency of about 1 in 100 000 cells), and retains the ability to differentiate into all types of blood cell. Hemopoiesis has been studied either by injecting small numbers of genetically marked marrow cells into recipient mice and observing the progeny they give rise to (in vivo cloning) or by culturing the bone marrow precursors in the presence of appropriate growth factors (in vitro cloning). Proliferation and differentiation of all these cells is under the control of soluble or membrane bound growth factors produced by the bone marrow stroma and by each other. Within the cell these signals switch on specific transcription factors, DNA-binding molecules which act as master switches that determine the subsequent genetic programme, in turn giving rise to development of the different cell types (known as lineages). Remarkably, recent studies have shown that it is possible to turn one differentiated cell type into another by experimentally introducing the right transcription factors into the cell. This finding has important therapeutic implications, e.g. in curing genetic immunodeficiencies. Most hemopoietic cells stop dividing once they are fully differentiated. However, lymphocytes divide rapidly and expand following exposure to antigen. The increased number of lymphocytes specific for an antigen forms the basis for immunological memory.
Figure 1. Immune cell development: the hemopoietic system
Bone marrow: Unlike most other tissues or organs, the hemopoetic system is constantly renewing itself. In the adult, the development of hemopoetic cells occurs predominantly in the bone marrow. In the fetus, before bones develop, hemopoeisis occurs first in the yolk sac and then in the liver.
Stroma: Epithelial and endothelial cells that provide support and secrete growth factors for hemopoiesis.
Stem cell: the totipotent and self-renewing marrow cell. Stem cells are found in low numbers in blood as well as bone marrow and the numbers can be boosted by treatment with appropriate growth factors (e.g. G-CSF), which greatly facilitates the process of bone marrow transplantation.
Lymphoid stem cell: presumed to be capable of differentiating into T or B lymphocytes. Very recent data suggest that the distinction between lymphoid and myeloid stem cells may in fact be more complex.
Hemopoietic stem cell: the precursor of spleen nodules and probably able to differentiate into all but the lymphoid pathways, i.e. granulocyte, erythroid, monocyte, megakaryocyte; often referred to as CFU-GEMM.
Erythroid stem cell: giving rise to erythrocytes. Erythropoietin, a glycoprotein hormone formed in the kidney in response to hypoxia, accelerates the differentiation of red cell precursors and thus adjusts the production of red cells to the demand for their oxygen-carrying capacity, a typical example of ‘negative feedback’.
Granulocyte–monocyte common precursor: the relative proportion of these two cell types is regulated by ‘growth-’ or ‘colony-stimulating’ factors.
Cloning: The potential of individual stem cells to give rise to one or more types of hemopoetic cells has been explored by isolating single cells and allowing them to divide many times, and then observing what cell types can be found among the progeny. This process is known as cloning (a clone being a set of daughter cells all arising from a single parent cell). Evidence suggests that in certain conditions a single stem cell can give rise to all the fully differentiated cells of an adult hemopoetic system.
Neutrophil (polymorph): The most common leucocyte in human blood, a short-lived phagocytic cell whose granules contain numerous bactericidal substances. Neutrophils are the first cells to leave the blood and enter sites of infection or inflammation.
Eosinophil: A leucocyte with large refractile granules that contain a number of highly basic or ‘cationic’ proteins, possibly important in killing larger parasites including worms.
Basophil: A leucocyte with large basophilic granules that contain heparin and vasoactive amines, important in the inflammatory response. The above three cell types are often collectively referred to as ‘granulocytes’.
Megakaryocyte: the parent cell of the blood platelets.
Platelets: Small cells responsible for sealing damaged blood vessels (‘hemostasis’) but also the source of many inflammatory mediators.
Monocyte: A precursor cell in blood developing into a macrophage when it migrates into the tissues. Additional monocytes are attracted to sites of inflammation, providing a reservoir of macrophages and perhaps also dendritic cells.
Macrophage: The principal resident phagocyte of the tissues and serous cavities such as the pleura and peritoneum.
DC (dendritic cell): Dendritic cells are found in all tissues of the body (e.g. the Langerhans’ cells of the skin) where they take up antigen and then migrate to the T-cell areas of the lymph node or spleen via the lymphatics or the blood. Their major function is to activate T-cell immunity, but they may also be involved in tolerance induction. A second subset of plasmacytoid DC (a name that derives from their morphological resemblance to plasma cells) are the principal producers of type I interferons, an important group of antiviral proteins. Although experimentally, dendritic cells are often derived from myeloid cells, the developmental lineage of dendritic cells in bone marrow is still the subject of debate.
NK (natural killer) cell: A lymphocyte-like cell capable of killing some virus-infected cells and some tumor cells, but with complex sets of receptors that are quite distinct from those on true lymphocytes (for more details see Fig. 10). NK cells and T cells may share a common precursor.
T and B lymphocytes: T (thymus-derived) and B (bone marrow derived or, in birds, bursa-derived) lymphocytes are the major cellular components of adaptive immunity. B lymphocytes are the precursor of antibody-forming cells. In fetal life, the liver may play the part of ‘bursa’.
Plasma cell: A B cell in its high-rate antibody-secreting state. Despite their name, plasma cells are seldom seen in the blood, but are found in spleen, lymph nodes, etc., whenever antibody is being made. Plasma cells do not divide and cannot be maintained for prolonged periods in vitro. However, B lymphocytes producing specific antibody can be fused with a tumor cell to produce an immortal hybrid clone or ‘hybridoma’, which continues to secrete antibody of a predetermined specificity. Such monoclonal antibodies have proved of enormous value as specific tools in many branches of biology, and several are now being used routinely for the treatment of autoimmune disease and cancer.
Mast cell: A large tissue cell derived from the circulating basophil. Mast cells are rapidly triggered by tissue damage to initiate the inflammatory response which causes many forms of allergy.
Growth factors: The molecules that control the proliferation and differentiation of hemopoietic cells are often also involved in regulating immune responses - the interleukins or cytokines. Some of them were first discovered by hematologists and are called ‘colony-stimulating factors’ (CSF), but the different names have no real significance, and indeed one, IL-3, is often known as ‘multi-CSF’. Growth factors are used in clinical practice to boost particular subsets of blood cell, and erythropoietin was one of the first of the new generation of proteins produced by ‘recombinant’ technology to be used in the clinic, and also by athletes wishing to increase their red cell numbers.