lymphopoiesis lymphopoiesis lymphopoiesis (lĭm'fō-poi-ē'sĭs) (or lymphocytopoiesis) is the generation of lymphocytes, one of the five types of white blood cells (wbcs). it is more formally known as lymphoid hematopoiesis. disruption in lymphopoiesis can lead to a number of lymphoproliferative disorders, such as lymphomas and lymphoid leukemias lymphopoiesis glossary • antigen any molecule that can provoke an immune defense • b cells lymphocytes that ultimately produce antibodies • bone marrow the center of bones capable of producing all red and white blood cells in the adult • cortex the outer portion of any organ • cytoplasm the portion of a cell between the nucleus and the membrane • differentiation permanent changes to a cell developing over time and with cell division • granules grains found in many white blood cells, composed of defensive chemicals • hematopoietic that which gives rise to any blood cell type • lineage a type of cell and its descendants by division and differentiation • lymphocytes a special 'lineage' of wbc • macrophages myeloid descendants (some may be lymphoid) with 'eating' abilities, also cooperate with lymphocytes • myeloid ancestors of wbcs with granules and also of macrophages • t cells "management" lymphocytes for immunity • (wbc) white blood cell in contrast to the much more common red blood cell; responsible for defense terminology lymphocytes are of the lymphoid (rather than the myeloid or erythroid) lineage of blood cells. immunology pioneer elie metchnikoff nomenclature is not trivial in this case, because, although lymphocytes are found in the bloodstream and originate in the bone marrow, they principally belong to the separate lymphatic system which interacts with the blood circulation. lymphopoiesis is now usually used interchangeably with the term "lymphocytopoiesis" - the making of lymphocytes - but other sources may distinguish between the two, stating that "lymphopoiesis" additionally refers to creating lymphatic tissue, while "lymphocytopoiesis" refers only to the creation of cells in that tissue. it is rare now for lymphopoiesis to refer to the creation of lymphatic tissues. myelopoiesis refers to 'generation of cells of the myeloid lineage' and erythropoiesis refers to 'generation of cells of the erythroid lineage' etc., so parallel usage has evolved in which lymphopoiesis refers to 'generation of cells of the lymphoid lineage'. observations on research going back well over 100 years had elucidated the two great classes of wbcs - myeloid and lymphoid - and great advances in medicine and science have resulted from these studies. it was only natural to ask where these two great classes of cells arose, and after much work two cell types with some strong stem cell properties were isolated and defined - cmp, the common myeloid progenitor and clp, the common lymphoid progenitor for mice. but science is an additive game and it was eventually found these progenitors were not unique, and further that the two great families of myeloid and lymphoid were not disjoint, but rather two partially interwoven family trees. this is more than just nomenclature, it is new science that provides challenges of complexity yet offers new vistas of bio-science and the promise of early enhancement of private and public health issues. and it gives insight into the nature of redundancy and overlap in the immune system and hints how to use this to advantage. purpose mature lymphocytes are a critical part of the immune system that (with the exception of memory b and t cells) have short lives measured in days or weeks and must be continuously generated throughout life by cell division and differentiation from cells such as common lymphoid progenitors (clps) in mice. the set comprising clp cells and similar progenitors are themselves descendants of the pluripotential hemopoietic stem cell (phsc) which is capable of generating all of the cell types of the complete blood cell system. despite their ability to generate the complete suite of lymphocytes, most progenitors are not true stem cells, however, and must be continually renewed by differentiation from the phsc stem cell. many progenitor cells are also referred to as transit cells, sometimes also called transit amplifying cells, the meaning of this term being that the transit cell may found a new sub-lineage but the number of resultant cells is strictly limited (although possibly very large, even trillions yet finite) and the lineage is terminated by cells that die off (by apoptosis) or remain as cells that can no longer divide. examples of such cells are cfus (colony-forming units - referred to as such because of their ability to form colonies in vitro in artificial media) such as cfu-t. in mice, transplantation of a single phsc cell can reconstitute a sub-lethally irradiated host (i.e. a mouse that has been irradiated so that all leukocytes are killed) with all these lineages of cells, including all types of lymphocytes via clps. this has been known for more than 40 years. lymphopoiesis continues throughout life and so progenitor cells and their parent stem cells must always be present. overview in the case of mammals such as humans (homo sapiens), lymphopoiesis begins with limited passive provision by the mother of lymphocytes and substantial immunoglobulin g that cross the placenta and enter the fetus to provide some protection against pathogens, and also leukocytes that come from breast milk and enter circulation via the digestive tract. it is often not effective in preventing infections in the newborn. however early in gestation the developing embryo has begun its own lymphopoiesis from the fetal liver. lymphopoiesis also arises from the yolk sac. this is in contrast to the adult where all lymphocytes originate in the bone marrow. there are four major types of lymphocytes, many sub-types, and hundreds or thousands of lymphocyte cell types that have been identified by scientists. all are generated by normal or abnormal lymphopoiesis except for certain artificial strains created in the laboratory by development from existing strains. although lymphocytes are usually considered mature (as seen in blood tests) they are certainly not inert but can and do get around the body to anywhere there is a need; and when such need arises, new rounds of 'downstream' lymphopoiesis such as cell multiplication and differentiation may arise, coupled with intense mitotic and metabolic activity. this is hardly a simple topic. in his 1976 text immunology, aging and cancer immunologist and nobel prize winner sir frank macfarlane burnet speculated that the immune system might one day be found to be as complex as the nervous system. as the production of lymphocytes is so close to the central role of the immune response it is wise to approach the study of it with some humility in the face of the task, although there are general principles that help in understanding. process lymphopoiesis acronyms • b-nk progenitor for b and nk • cb cord blood • cfu colony-forming unit • clp common lymphoid progenitor • cmp common myeloid progenitor • dc dendritic cell (myeloid or lymphoid) • elp early lymphoid progenitors • etp the most primitive cells in the thymus are the early thymocyte progenitors • g-csf granulocyte colony stimulating factor • gm-csf granulocyte macrophage colony stimulating factor • gmp granulocyte macrophage progenitor; • hsc pluripotential hemopoietic stem cell • mdc combined macrophage and dc progenitor potential • mep megakaryocytic and erythroid progenitor • mlp multi-lymphoid progenitor potential, any progenitor minimally able to give rise to b cells, t cells and nk cells • mpp multipotent progenitor • notch notch signaling pathway re t cell commitment from progenitors lymphopoiesis can be viewed in a mathematical sense as a recursive process of cell division and also as a process of differentiation, measured by changes to the properties of cells. given that lymphocytes arise from specific types of limited stem cells - which we can call p (for progenitor) cells - such cells can divide in several ways. these are general principles of limited stem cells. considering the p as the ‘mother’ cell, but not a true stem cell, it may divide into two new cells, which are themselves identical, but differ to some degree from the mother. or the mother cell p may divide unequally into two new daughter cells both of which differ from each other and also from the mother. any daughter cell will usually have new specialized abilities and if it is able to divide it will form a new sub-lineage. the difference of a daughter cell from the mother may be great, but it could also be much less, even subtle. what the p mother cell does not do is divide into two new p mother cells or a mother and a daughter; this is a matter of observation as such limited progenitor cells are known to not self-renew. there is a sort of exception when daughter cells at some level of the lineage may divide several times to form more seemingly identical cells, but then further differentiation and division will inevitably occur, until a final stage is reached in which no further division can occur and the cell type lineage is finally mature. an example of maturity is a plasma cell, from the b cell lineage, which produces copious antibody, but cannot divide and eventually dies after a few days or weeks. the progenitor clp of the mouse or the progenitor mlp of the human differentiates into lymphocytes by first becoming a lymphoblast (medical immunology, p.10). it then divides several more times to become a prolymphocyte that has specific cell-surface markers unique to either a (1) t cell or (2) b cell. the progenitor can also differentiate into (3) natural killer cells (nks) and (4) dendritic cells (dcs). t cells, b cells and nk cells (and all other innate lymphoid cells) are unique to the lymphocyte family, but dendritic cells are not. dcs that are of identical appearance but have different markers are spread throughout the body, and come from either lymphoid and myeloid lineages, but these cells may have somewhat different tasks and may take up lodging preferentially in different locations. (revise in light of new research) this is now an open question; also, the different dendritic cell lineages may have different ‘tasks’ or functions, and stay in different ‘locations.’ t and b lymphocytes are indistinguishable under the microscope. the inactive b and t cells are so featureless with few cytoplasmic organelles and mostly inactive chromatin that until the 1960s textbooks could describe these cells, now the central focus of immunology, as having no known function! however t and b lymphocytes are very distinct cell lineages and they ‘grow up’ in different places in the body. they perform quite different (although co-operative) functions in the body. no evidence has ever been found that t and b cells can ever interconvert. t and b cells are biochemically distinct and this is reflected in the differing markers and receptors they possess on their cell surfaces. this seems to be true in all vertebrates, although there are many differences in the details between the species. regardless of whether the clp (mouse) or mlp or a small closely related set of progenitor cells take credit for generating the profusion of lymphocytes, the same lymphoid progenitors can still generate some cells that are clearly identifiably myeloid. lymphopoiesis for t cells t cells are formed in bone marrow then migrate to the cortex of the thymus to undergo maturation in an antigen-free environment for about one week where a mere 2–4% of the t cells succeed. the remaining 96–98% of t cells die by apoptosis and are phagocytosed by macrophages in the thymus. so many thymocytes (t cells) die during the maturation process because there is intensive screening to make sure each thymocyte has the ability to recognize self-peptide:self-mhc complex and for self tolerance. the apoptosed thymocyte dies and is quickly recycled. upon maturity, there are several forms of thymocytes including t-helper (needed for activation of other cells such as b cells and macrophages), t-cytotoxic (which kill virally infected cells), t-memory (t cells that remember antigens previously encountered), and t-suppressor cells (which moderate the immune response of other leukocytes). also called t-regulatory cells (treg) when t cells become activated they undergo a further series of developments. a small, resting t lymphocyte rapidly undergoes blastogenic transformation into a large lymphocyte (13–15 μm). this large lymphocyte (known in this context as a lymphoblast) then divides several times to produce an expanded population of medium (9–12 μm)