Active immune system cells originate from hematopoietic stem cells produced by the bone marrow, but are conveyed within blood to different tissues in the body. There are two major lineages. The lymphoid lineage leads to lymphocytes and the related natural killer (NK) cells. The myeloid lineage leads to the other types of immune system cell, including both blood cells (the granulocytes—neutrophils, eosinophils, and basophils— and monocytes) and different tissue cells (macrophages, dendritic cells, and mast cells).
Another branch of the myeloid lineage gives rise to red blood cells, megakaryocytes, and platelets (Figure 1).
Fig1. Hematopoietic stem cells in the bone marrow give rise to all blood cells and to different tissue cells with immune system functions. The multipotent hematopoietic stem cell shown at the top divides and differentiates to give more specialized progenitor cells. A lymphoid precursor gives rise to B and T lymphocytes of the adaptive immune system and natural killer (NK) cells of the innate immune system. The myeloid precursor gives rise to other classes of immune system cell, and also an erythroid lineage ultimately producing red blood cells and platelets. Macrophages and dendritic cells work in tissues and are important not just in the innate immune system, but also when they act as antigen-presenting cells in the adaptive immune system. Mast cells are another type of tissue cell and seem to be the tissue equivalent of the basophils in blood. Note: data from recent whole-genome sequencing studies are incompatible with the monophyletic theory, in which all blood cells were envisaged to arise from a common stem cell. Instead they suggest that blood cells are founded by multiple stem cells with polyphyletic ancestry. (Adapted from Parham P [2014] The Immune System, 4th edn. Garland Science. With permission from WW Norton.)
B and T lymphocytes
These lymphocytes, the central players of the adaptive immune system, originate in two primary lymphoid tissues: the bone marrow (where B cells complete their maturation before entering the circulation) and the thymus (immature T cells migrate from the bone marrow through the bloodstream to the thymus where they mature).
B and T cells were called lymphocytes because, unlike other blood cells, they can also circulate in the lymph, the extracellular fluid that bathes tissues. They become concentrated in multiple different secondary lymphoid tissues where they are stimulated to respond to invading pathogens. Among these peripheral lymphoid tissues are multiple lymph nodes and the spleen; following an infection, the spleen acts to filter foreign anti gen from the blood, and lymph nodes filter foreign antigen from lymph. Both the spleen and lymph nodes are packed with mature immune cells, predominantly lymphocytes, but they also contain macrophages, dendritic cells, and other cells. See Figure 2 for the other principal locations of secondary lymphoid tissue.
Fig2. Locations of principal lymphoid tissues within the human body. The primary lymphoid organs are where B and T cells are produced: B cells complete their maturation in the bone marrow, but immature T cells migrate from the bone marrow in the blood to the thymus to complete their development. Secondary lymphoid tissues are where mature B and T cells encounter foreign antigen, which stimulates them to respond to invading pathogens and initiate adaptive immune responses. The secondary lymphoid tissues include lymph nodes (which filter antigens from lymph) and the spleen (which filters antigens from blood). The lymph nodes lie at junctions of a network of lymphatic vessels (also called lymphatics), with significant aggregates found close to the skin in the neck, armpit, and groin regions. (The lymphatics originate in the connective tissues of the body; they collect the plasma that is constantly leaking out of blood vessels to form the extracellular fluid, lymph, that bathes tissues, eventually returning the lymph to the blood.) Rather less organized mucosa-associated lymphoid tissue is found in various sites. Gut-associated lymphoid tissue (tonsils, adenoids, Peyer’s patches in the small intestine, and lymphoid aggregates in the appendix and large intestine) collectively constitutes the largest lymphoid organ, consistent with its need to interact with a huge load of antigens from food and commensal bacteria. Epithelial-associated lymphoid tissue is also found in the skin and in the mucous membranes lining the upper airways, bronchi, and genitorurinary tract. (Adapted from Parham P [2014] The Immune System, 4th edn. Garland Science. With permission from WW Norton.)
B cells are distinguished by the making of immunoglobulins (Ig). Early (“naive”) B cells (B lymphoblasts) make IgM or IgD immunoglobulins that are incorporated into the cell membrane (a transmembrane B-cell receptor). After exposure to antigens, however, the B lymphoblasts are stimulated primarily in the lymph nodes to make effector B cells known as plasma cells. Instead of making a membrane-bound B-cell receptor, plasma cells secrete soluble immunoglobulins (IgM, IgG, IgA, or IgE classes) as antibodies that can recognize a specific antigen and combat bacterial infection in ways that we describe below.
T cells are distinguished by the making of a transmembrane receptor known as a T-cell receptor. The job of effector T cells is to recognize and deal with sick or damaged host cells that express foreign antigen on their cell surface, including, notably, virus infected cells. To do that, they are assisted by certain antigen-presenting cells that present the foreign antigen on the cell surface as a complex with a major histocompatibility complex (MHC) protein. As described below, cytotoxic T lymphocytes induce the death of the harmful body cells, but various other types of effector T cells help in the process.
Natural killer (NK) cells
NK cells are large, lymphocyte-like effector cells of the innate immune system and are important in the defense against viral infections. Their job is to enter infected tissues and limit the spread of the infection in two ways: by killing body cells infected by the virus, and by secreting certain types of cytokine to impede viral replication in host cells.
Granulocytes (polymorphonuclear leukocytes)
As the name suggests, these white blood cells have prominent cytoplasmic granules and irregularly shaped nuclei (usually with two to five lobes). The cytoplasmic granules contain assorted antimicrobial reagents—defensins (peptides that insert into and then disrupt the cell membranes of pathogens), lysozyme, myeloperoxidase, and so on—that can be secreted as required. There are three types of granulocyte, as listed below.
• Neutrophils are the most common type of white blood cell, and an important effector cell of the innate immune system. They are also the most abundant and most lethal type of phagocyte (a cell that specializes in engulfing and killing a microbial pathogen; see Figure 3). Large reserves of neutrophils are stored in the bone marrow and are mobilized when needed to fight infection. They travel in the bloodstream and from there to infected tissues where they engulf and kill bacteria, but they are short-lived and die at the infection site, forming pus.
• Eosinophils are comparatively rare (1–6% of white blood cells) and protect against helminth worms and other intestinal parasites.
• Basophils are very rare and also protect against parasites, being recruited into tissues at sites of infection.
Fig3. How immune system phagocytes kill microbial pathogens. (A) A single neutrophil (yellow) engulfing rod-shaped anthrax bacilli (orange). Like other phagocytes, neutrophils engulf microbial pathogens, which are then destroyed within the phagocyte. (B) Immune system phagocytes, such as macrophages, have cell surface receptors that can recognize certain types of pattern on microbes (such as components of bacterial cell walls), identifying them as foreign cells. The process of phagocytosis begins with binding of a bacterium (or other microbe) by cell surface receptors, followed by internalization of the microbe within a vacuole called a phagosome. Lysosomes fuse with phagosomes to form phagolysosomes and then discharge their hydrolytic enzymes and dangerous chemicals to degrade the microbe. A signal-transduction pathway is also triggered when the pattern-recognition receptor binds the pathogen, resulting in activated transcription of genes that make inflammatory cytokines. The secreted cytokines bind to surface receptors on other immune system cells, recruiting them to participate in the immune response. (A, original image by Volker Brinkmann [2005] PLoS Pathog 1(3):cover page; B, used with permission from Dr Victoria J Drake and Linus Pauling Institute Micronutrient Information Center at Oregon State University.)
Monocytes and macrophages
Monocytes account for about 2–10% of circulating white blood cells and are also abundant in the spleen. They are bigger than granulocytes and have a more consistent appearance with a distinctive indented nucleus. They are a class of free-roaming phagocyte and they also give rise to long-lived, specialized tissue phagocytes known as macrophages, the general scavenger cells of the body that are particularly active in phagocytosing dead cells and debris as well as invading microorganisms.
Tissue macrophages arise after monocytes respond to inflammation signals: the monocytes migrate rapidly in the blood and enter tissues at infection sites, whereupon they differentiate. According to the tissue that they inhabit, tissue macrophages can be known by other names, such as Kupffer cells (liver), microglia (brain and spinal cord), and osteoclasts (bone).
Dendritic cells and mast cells
Dendritic cells are star-shaped tissue immune cells with many of the properties of macrophages, but their main purpose is to act as messenger cells: when required, they are sent to summon up an adaptive immune response. If the initial innate immune response to infection seems to be inadequate, dendritic cells within the infected tissue migrate to one of the secondary lymphoid tissues that specialize in making adaptive immune responses.
Mast cells are granulated cells that seem to be the tissue equivalent of basophils, being present in all connective tissues. When activated at sites of infection they release their cytoplasmic granules (degranulation). They are important in inflammation and allergic responses.
