Innate Immune Cells

Innate immune cells circulate freely in blood or reside in tissues and are poised to respond rapidly to invading pathogens or inflammatory stimuli. While some innate immune cells remain in situ throughout their lifetime, others can migrate to lymphoid tissues to invoke T and B cell responses.

Monocytes

Monocytes are the largest of the leukocytes (white blood cells) and, like all leukocytes, are derived from hematopoietic stem cells in the bone marrow. Following their production, monocytes are released into the blood, where they make up around 5% of the circulating cell population and have a half-life of approximately 3 days. One of the main functions of monocytes is to phagocytose pathogens, either through direct binding to pattern recognition receptors (PRRs) on the pathogen surface, or by interacting with pathogen-bound antibodies via monocyte Fc receptors. Monocytes also have the ability to mature into macrophages and dendritic cells, and can produce a broad range of cytokines to activate other immune cells.

Macrophages

Macrophages are derived from monocytes that leave the circulation to differentiate in various tissues. They can be classified according to their location, with examples including alveolar macrophages (lung), Kupffer cells (liver), and microglia (central nervous system). Importantly, some tissue-resident macrophages have the capacity to replenish themselves directly from local precursors, allowing them to maintain cell numbers following depletion. The primary role of macrophages is to detect and phagocytose pathogens, which they achieve through mechanisms such as using toll-like receptors (TLRs) to recognize different pathogen components. Other macrophage functions include presenting antigens to T cells and initiating inflammation through cytokine release.

Dendritic Cells

Dendritic cells are derived from the same lineage as macrophages and, like macrophages, are professional antigen-presenting cells (APCs) that bridge the innate and adaptive immune systems. The APC function of dendritic cells is superior to that of macrophages, partly due to their high surface area which enables them to contact a greater number of surrounding cells. After leaving the bone marrow and entering the circulation, dendritic cell precursors migrate to the peripheral tissues, where they continually sample their environment for the presence of foreign invaders. Upon detecting a pathogen via mechanisms including toll-like receptor (TLR) or Fc receptor binding, dendritic cells mature as they migrate to the lymph nodes, subsequently presenting the bound antigen to T cells for development of the immune response.

Natural Killer Cells

Natural killer (NK) cells were named for their ability to destroy tumor cells without the need for priming by APCs. They achieve this by releasing cytotoxic granules containing biomolecules such as perforin and granzymes to lyse their targets, a process that is often driven by cells having lost their MHC class I molecules, meaning they are no longer identified as ‘self’. NK cells destroy tumor cells and virally-infected cells via the same process. NK cells develop and mature in the bone marrow and in secondary lymphoid tissues like the spleen and tonsils, and make up 5-20% of all the circulating lymphocytes in the blood. In addition to their cell killing function, NK cells secrete a broad range of cytokines and chemokines to modulate the activity of other immune cells.

Granulocytes

Granulocytes comprise four main cell types - neutrophils, eosinophils, basophils, and mast cells. They are the first cells to be recruited to the site of an infection and have an essential role in initiating the innate immune response. Neutrophils are the most abundant granulocytes, representing around 40-60% of all circulating leukocytes, and can both phagocytose pathogens or destroy them by releasing granules containing anti-microbial factors such as hydrolase enzymes. Eosinophils make up just 1% of circulating leukocytes and are recruited into tissues at sites of inflammation; here, they release an array of inflammatory mediators to regulate the immune response. Basophils are similar in abundance to eosinophils and are produced in response to parasitic infections; they are also involved in the allergic response, releasing histamine following activation by antigen crosslinking of FcεRI receptor-bound IgE. A main difference between mast cells and other granulocytes is that mast cells reside in mucosal and epithelial tissues rather than in the blood; they are primarily involved in the IgE-dependent allergic response and their granules contain inflammatory mediators that include histamine, heparin, and serotonin.

Adaptive Immune Cells

Adaptive immune cells comprise B cells and T cells, which were originally named according to where they mature. While both cell types are produced in the bone marrow, only B cells mature here; T progenitor cells instead mature in the thymus. Critically, adaptive immune cells are involved in the development of immune memory, which enables a faster and more robust response to a pathogen during any subsequent encounter.

T cells

T cells can broadly be divided into CD4+ cells and CD8+ cells, better known as T helper cells and cytotoxic T cells, respectively. Of these, it is the CD4+ cells that are involved in the adaptive immune response; CD8+ cells instead destroy virally-infected cells or tumor cells by releasing cytotoxic granules, producing cytokines such as TNF-α and IFN-γ, and activating the caspase cascade via Fas/FasL signaling. CD4+ cells comprise various subsets, including Th1, Th2, Th17 and Treg cells, all of which produce different cytokines and perform distinct functions.

B cells

B cells are antibody-producing cells that circulate freely in the blood until they encounter their specific antigen. Upon antigen binding to the B cell receptor (a unique antibody expressed at the B cell surface), B cells undergo rapid cell division to form effector B cells (plasma cells) and memory B cells. Plasma cells secrete antibodies that bind to the foreign pathogen and facilitate its destruction via mechanisms that include phagocytosis by macrophages and lytic destruction by neutrophils. Memory B cells instead remain in circulation for many years, undergoing immediate clonal expansion upon re-encountering the pathogen to protect against any adverse effects. Another subset of B cells known as regulatory B cells (Bregs) has more recently been discovered; these produce IL-10, IL-35, and transforming growth factor β (TGF-β) to suppress the immune response.