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.
Overview
Lymphocytes are blood cells of lymphoid (rather than the myeloid or erythroid) lineage. Lymphocytes are found in the bloodstream and originate in the bone marrow, however, 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 some sources 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.
The two classes of WBCs in mice originate from progenitor cells: myeloids from the common myeloid progenitor (CMP), and lymphoids from the common lymphoid progenitor (CLP).
In the case of mammals such as humans (Homo sapiens), lymphopoiesis begins with limited passive provision from the mother. This includes lymphocytes and immunoglobulin G that cross the placenta and enter the fetus to provide some protection against pathogens, as well as 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.Adult T-cell Progenitors Retain Myeloid Potential; Nature; 2008 This is in contrast to the adult where all lymphocytes originate in the bone marrow.Textbook of Human Development and Histology, p.176
There are four major types of lymphocytes, along with many sub-types.
Function
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.Stem Cell Biology, page 307 Despite their ability to generate the complete suite of lymphocytes, most progenitors are not true stem cells, and must be continually renewed by differentiation from the pHSC stem cell.
Many progenitor cells are also referred to as transit cells,Dynamics of Cancer, page 251 sometimes also called transit amplifying cells, the meaning of this term being that the transit cell may find 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.
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.
Lymphopoiesis continues throughout life and so progenitor cells and their parent stem cells must always be present. Process
Lymphopoiesis is a recursive process of cell division and also as a process of differentiation, measured by changes to the properties of cells. The function of lymphopoiesis is the production of various lymphocytes from common lymphoid progenitor (CLP) cells, which are in turn derived from hematopoietic stem cells.
Division and differentiation
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 (NK) and (4) dendritic cells (DC). T cells, B cells and NK cells (and all other Innate lymphoid cells) are unique to the lymphocyte family, but dendritic cells are not. DC that are of identical appearance but have different markers are spread throughout the body, and come from either lymphoid and myeloid lineages. Still, these cells may have somewhat different tasks and may take up lodging preferentially in different locations.Immuno-Biology, The Immune System in Health and Science. (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.’ Fundamental Immunology 5th edition
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 they were believed to have no function; they were recognized to have key immune functions in the 1960s.Immuno-Biology, The Immune System in Health and Science. Garland Science Publishing
However, T and B lymphocytes are very distinct cell lineages and they mature in different places in the body. They perform quite different (although co-operative) functions in the body. 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 and 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 can recognize self-peptide:self-MHC complex and for self-tolerance. Having experienced apoptosis, the thymocyte dies and is quickly recycled.
Upon maturity, there are several forms of thymocytes including Textbook of Medical Immunology, page 5 T-helper (needed for activation of other cells such as B cells and macrophages), T-cytotoxic (which kills 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) and small lymphocytes (5–8 μm) with the same antigenic specificity.Medical Immunology, page 23 Final activated and differentiated T lymphocytes are once again morphologically indistinguishable from a small, resting lymphocyte. Thus the following developmental states may be noticed in sequence in blood tests: Prolymphocyte Large lymphocyte Small lymphocyte
Basic Map of T Cell lymphopoiesis
This basic map of T Cell formation in sequence, is simplified and is akin to textbook descriptions, and may not reflect latest research. (Medical Immunology, p. 119)
In the thymus MLP ETP DN1 (B; Mφ) DN2 (DC; NK) DN3 (γδ) DN4 DP (TNK; CD4; CD8; Treg)
In the Periphery (Th1; Th2)
T cell development
Unlike other lymphoid lineages, T cell development occurs almost exclusively in the thymus. T-lymphopoiesis does not occur automatically but requires signals generated from the thymus stromal cells. Several stages at which specific regulators and growth factors are required for T cell development to proceed have been defined. Later in T cell development and its maturation, these same regulatory factors again are used to influence T cell specialization.
T cells are unique among the lymphocyte populations in their ability to further specialize as mature cells and become yet more mature. T cells come in many flavors, for example: the conventional TcRαβ T cells; the so-called unconventional TcRγδ T cells; NKT cells; and T regulatory cells (Treg). Details regarding the developmental and life cycle of the unconventional T cells are less well-described measured to the conventional T cells.
Stages of T cell maturation
Stage One: Thymus Migration
Multi-potent lymphoid progenitors (MLP) enter the T cell pathway as they immigrate to the thymus. The most primitive cells in the thymus are the early thymocyte progenitors (ETP), which retain all lymphoid and myeloid potential but exist only transiently, rapidly differentiating into T and NK lineages. (Medical Immunology, p. 118)
Stage Two: Proliferative Expansion and T Lineage Commitment
Final commitment to the T cell lineage occurs within the thymus microenvironment, the microscopic structures of the thymus where T cells are nurtured. The most primitive T cells retain multipotential ability and can differentiate into cells of the myeloid or lymphoid lineages (B cells, DC, T cells, or NK cells).
More differentiated double negative T cells (DN2 cells) have more limited potentiality but are not yet fully restricted to the T cell lineage (they can still develop into DC, T cells, or NK cells). Later on, they are fully committed to the T cell lineage- when thymocytes expressing Notch1 receptors engage thymus stromal cells expressing Notch1 ligands, the thymocytes become finally committed to the T-cell lineage. See Gallery Image "Double Negatives"