and small lymphocytes (5–8 μm) with the same antigenic specificity. 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 thymic 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. and 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 compared to the conventional t cells. stages of t cell maturation stage one: thymic migration multipotent 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 thymic microenvironment, the microscopic structures of the thymus where t cells are nurtured. the most primitive t cells retain pluripotential 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 thymic stromal cells expressing notch1 ligands, the thymocytes become finally committed to the t-cell lineage. see gallery image "double negatives" with the commitment to the t cell lineage, begins a very complex process known as tcr gene rearrangement. this creates an enormous diversity of t cells bearing antigen receptors. afterward some t cells leave the thymus to migrate to the skin and mucosae. stage three: β-selection stage four: t cell receptors selection only 2% to 3% of the differentiating thymocytes, those that express tcr capable of interaction with mhc molecules, but tolerant to self-peptides, survive the stage four selection process. stage five: continuing differentiation in the periphery it was previously believed that the human thymus remained active as the site of t cell differentiation only until early adulthood and that later in adult life the thymus atrophies, perhaps even vanishing. recent reports indicate that the human thymus is active throughout adult life. thus several factors may contribute to the supply of t cells in adult life: generation in the thymus, extra-thymic differentiation, and the fact that memory t cells are long-lived and survive for decades. t cell types unconventional t cells the thymus also gives rise to the so-called ‘unconventional t cells’ such at γδ t cells, natural killer t cells (nkt) and regulatory t cells (treg). γδ t cells γδt cells represent only 1% to 5% of the circulating t cells, but are abundant in the mucosal immune system and the skin, where they represent the dominant t cell population. these ‘non-mhc restricted t cells’ are involved in specific primary immune responses, tumor surveillance, immune regulation and wound healing. several differences between αβ and γδ t cell development have been described. they emigrate from the thymus in "waves" of clonal populations, which home to discrete tissues. for example, one kind is found in the peripheral blood while another predominates in the intestinal tract. natural killer t cells human nkt cells are a unique population and are thought to play an important role in tumor immunity and immunoregulation. t regulatory cells treg cells are considered as naturally occurring regulatory t cells. tregs comprised about 5% of the circulating cd4+ t cells. these cells are thought to possess an important autoimmunity property by regulating 'autoreactive' t cells in the periphery. (medical immunology, p. 117-122) lymphopoiesis for b cells b cells are formed and mature in bone marrow (and spleen). it is a good mnemonic aide that b cells are formed in the bone marrow, but it is a mere coincidence since b cells were first studied in the chicken's bursa of fabricius and it is from this bursa that b cells get their name. these b cells then leave the bone marrow and migrate via bloodstream and the lymph to peripheral lymphoid tissues, such as a spleen, lymph nodes, tonsils and mucosal tissues. once in a secondary lymphoid organ the b cell can be introduced to an antigen that it is able to recognize. through this antigen recognition and other cell interactions the b cell becomes activated and then divides and differentiates to become a plasma cell. the plasma cell, a b cell end product, is a very active antibody-secreting cell that helps protect the body by attacking and binding to antigen. even after many decades of research, some controversy remains as to where b cells mature and 'complete their education', with the possibility remaining that the site may also partially be peri-intestinal lymphoid tissues. b lymphopoiesis occurs exclusively in the bone marrow and b lymphocytes are made continuously throughout life there in a 'microenvironment' composed of stromal cells, extracellular matrix, cytokines and growth factors, which are critical for proliferation, differentiation, and survival of early lymphocyte and b-lineage precursors. the relative proportion of precursor b cells in the bone marrow remains rather constant throughout the life span of an organism. there are stages such as pre-b-i cells (5% to 10% of the total); pre-b-ii cells (60% to 70%) while the remaining 20% to 25% are immature b cells. most textbooks say that b cells mature in the bone marrow but, generally, immature b cells migrate to the spleen for 'higher education' of some sort where they go through transitional stages before final maturation.(medical immunology, p. 136) b lymphocytes are identified by the presence of soluble immunoglobulin g (igg). this is the most common protective immunoglobulin in the adult body. after antigenic stimulation, b cells differentiate into plasma cells that secrete large quantities of soluble igg. this is the final stage of b lymphopoiesis but it is the clincher because the plasma cells must either issue antibody close to a source of infection, or disseminate it in the blood to fight an infection at a distance or in an inaccessible part of the body. basic map of b cell lymphopoiesis early b cell development: from stem cell to immature b cell transitional b cell development: from immature b cell to mz b cell or mature fo b cell. a generally regarded valid map of b cell lymphopoiesis is as follows in sequence, in two parts with the first being in the bone marrow and the second in the spleen:. the development process in the bone marrow occurs in germinal centers in the bone marrow pro-b pre-b-i pre-b-ii large pre-b-ii small imm(ature) in the spleen t1 t2/t3 (marginal zone (mz); b-1; b-2) b-2 further differentiate into: (germinal center (gc); memory; plasma ) lymphopoiesis for nk cells nk cells, which lack antigen specific receptors, develop in the bone marrow. after maturation and release from the marrow they circulate in the blood through their lifetime seeking opportunity. the opportunity they seek is to encounter and recognize and then kill abnormal cells such as cancer or virally infected cells. it is well known that lymphocytes never have granules or at least not granules that are readily visible even upon staining. however nk cells are the exception. they do have numerous granules which provide their ability to kill cells and these granules are why nk cells have an alternate name- large granular lymphocytes (lgls). nk cells are the only lymphocytes considered part of the innate immune system (in contrast to the adaptive immune system. yet they are much more closely related to t cells (part of the adaptive immune system) than to other cells of the innate immune system. nk cells not only share many surface markers, functions and activities in common with t cells, they also arise from a common t/nk progenitor. the t/nk precursor is also believed to be the source of a subpopulation of lymphoid dc. (medical immunology, p. 121) nk cells have a definition 'barcode' as cd3, cd16+, cd56t lymphocytes. (see barcode section of this article). nk progenitors can be found mainly in the thymus (mouse), but the thymus is not absolutely required for nk development. probably nk cells can develop in a variety of organs but the major site of nk cell development is not known. in humans, the majority (85–90%) of the nk cells have a high cytolytic capacity (the ability to lyse cells). a smaller subset (10–15%) called nk 'cd56 bright' is chiefly responsible for cytokine production and has enhanced survival. traveling to lymph nodes the 'cd56 bright' nk cells differentiate again into mature nk cells which express killer cell immunoglobulin-like receptors (kir), natural cytotoxicity receptors (ncr), and critical adhesion molecules. (medical immunology, p. 122) lymphopoiesis for dendritic cells the process by which clp cells may differentiate to generate dendritic cells of lymphoid lineage is not yet well defined. dcs are highly specialized and efficient antigen-presenting cells. cells identical in appearance come both from a myeloid lineage (referred to as myeloid dendritic cells) and also from a lymphoid lineage (referred to as plasmacytoid dendritic cells). the development and regulation of dc is not well-characterized. while the dc precursors have been identified in the human fetal liver, thymus, and bone marrow, during adult life dc are thought to be produced only from the bone marrow and released into the blood to wander and settle down. overall a large number of dc of varying types are dispatched throughout the body, especially at epithelia such as skin, to monitor invaders and nibble their antigens. (medical immunology, p. 122) comparison of killers from lymphopoiesis lymphocytes have a number of alarming properties such as the ability to wander around the body and take up lodging almost anywhere, and while on the way issue commands in the form of cytokines and chemokines and lymphokines, commands that affect many cell types in the body and which may also recursively induce further lymphopoiesis. one strong behavior pattern that captivates researchers and the public alike is the ability of lymphocytes to act as police, judge and executioner to kill other cells or demand that they suicide, a command that is usually obeyed. there seems to be no other sentencing option available. killers are distinguished from cells such as macrophages that eat other cells or munch debris by a method called phagocytosis. killers do not use phagocytosis, they just kill and leave the clean-up to other cells. killers are known to attack virus-infected cells and cells that have become cancerous. because of these abilities much research has been done into transforming these qualities into medical therapy but progress has been slow. here is the parade of killers and how they work: cytotoxic t cells (also called tc or antigen-specific cyto -lytic or -toxic t lymphocytes (ctl)). tc kill by apoptosis and either splash their target with perforin or granzymes or else use fas-fasl interaction to command target elimination. this kills cells that are infected and display antigen. nk cells (also called lgl (large granular lymphocytes)) these kill with exactly the same methods as tc, but have no interaction with any antigen. they select their targets based on typical molecules displayed by cells that are under stress by viral infection. nk