Education and activation

Site of lymphocyte production - Bone marrow. After reproduction, lymphocytes are concentrated in the thymus gland, called the thymus. Here lymphocytes undergo a series of changes, leading to their division into several subtypes. T lymphocytes provide invaluable assistance to the immune system by fighting viral antibodies. When any pathologies or viral infections appear, T-lymphocytes are activated, the function of which is activated through IL-1 and CD-3 receptor connections.

Functions of T lymphocytes

When acquiring a particular viral or infectious disease, T-lymphocytes are brought into active action.

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Anna Poniaeva. She graduated from the Nizhny Novgorod Medical Academy (2007-2014) and Residency in Clinical Laboratory Diagnostics (2014-2016).

Depending on the type of viral cells, certain types of “T” type leukocytes are included in the work. The type of leukocytes under the letter “B” has an impressive memory for various “enemy” microbodies. The function of leukocytes of this group is precisely to remember infected “guests” who have already visited, and to give a signal for the activation of T-lymphocytes.

In the process of evolution, humans have developed two immune systems - cellular and humoral. They arose as a means of combating substances that are perceived as foreign. These substances are called antigens. In response to the introduction of an antigen into the body, depending on the chemical composition, dose and form of administration, the immune reaction will be different: humoral or cellular. The division of immune functions into cellular and humoral is associated with the existence of T- and B-lymphocytes. Both lineages of lymphocytes develop from a lymphatic stem cell in the bone marrow.

T lymphocytes. Cellular immunity. Thanks to T-lymphocytes, the body's cellular immune system occurs. T lymphocytes are formed from hematopoietic stem cells that migrate from the bone marrow to the thymus gland.

The formation of T lymphocytes is divided into two periods: antigen-independent and antigen-dependent. The antigen-independent period ends with the formation of antigen-reactive T lymphocytes. During the antigen-dependent period, the cell prepares to encounter the antigen and multiplies under its influence, resulting in the formation of various types of T cells. Antigen recognition occurs due to the fact that on the membrane of these cells there are receptors that recognize antigens. As a result of recognition, cells multiply. These cells fight against antigen-carrying microorganisms or cause rejection of foreign tissue. T cells regularly move from lymphoid elements into the blood and interstitial environment, which increases the likelihood of them encountering antigens. There are different subpopulations of T lymphocytes: killer T cells (i.e. fighters), which destroy cells with antigen; T helper cells, which help T and B lymphocytes respond to antigens, etc.

T-lymphocytes, upon contact with an antigen, produce lymphokines, which are biologically active substances. With the help of lymphokines, T lymphocytes control the function of other leukocytes. Various groups of lymphokines have been identified. They can both stimulate and inhibit the migration of macrophagocytes, etc. Interferon produced by T lymphocytes inhibits the synthesis of nucleic acids and protects the cell from viral infections.

B lymphocytes. Humoral immunity. During the antigen-dependent period, B lymphocytes are stimulated by the antigen and settle in the spleen and lymph nodes, follicles and reproduction centers. Here they are converted to plasma cells. The synthesis of antibodies - immunoglobulins - occurs in plasma cells. Humans produce five classes of immunoglobulins. B lymphocytes take an active part in the immune processes of antigen recognition. Antibodies interact with antigens located on the surface of cells or with bacterial toxins and accelerate the uptake of antigens by phagocytes. The antigen-antibody reaction is the basis of humoral immunity.

During an immune response, both humoral and cellular immunity mechanisms are usually at work, but to varying degrees. Thus, with measles, humoral mechanisms predominate, and with contact allergies or rejection reactions, cellular immunity predominates.

A well-functioning immune system of a healthy person is able to cope with most external and internal threats. Lymphocytes are blood cells that are the first to fight for the cleanliness of the body. Viruses, bacteria, fungus are the daily concern of the immune system. Moreover lymphocyte functions are not limited to detecting external enemies.

Any damaged or defective cells of one's own tissues must also be detected and destroyed.

Functions of lymphocytes in human blood

The main performers in the work of immunity in humans are colorless blood cells - leukocytes. Each variety fulfills its function, most important of which are allocated specifically to lymphocytes. Their number relative to other leukocytes in the blood sometimes exceeds 30% . Functions of lymphocytes are quite diverse and accompany the entire immune process from beginning to end.

In essence, lymphocytes detect any fragments that do not correspond to the body genetically, give a signal to start a battle with foreign objects, control its entire course, actively participate in the destruction of “enemies” and end the battle after victory. As conscientious guards, they remember each violator by sight, which gives the body the opportunity to act faster and more efficiently at the next meeting. This is how living beings manifest a property called immunity.

The most important lymphocyte functions:

1. Detection of viruses, bacteria, other harmful microorganisms, as well as any abnormal cells of one’s own body (old, damaged, infected, mutated).
2. A message to the immune system about the “invasion” and the type of antigen.
3. Direct destruction of pathogenic microbes, production of antibodies.
4. Management of the entire process using special “signal substances”.
5. Winding down the active phase of the “battle” and managing the cleanup after the battle.
6. Preservation of memory of each defeated microorganism for subsequent rapid recognition.

The production of such immune soldiers occurs in the red bone marrow; they have different structures and properties. It is most convenient to distinguish immune lymphocytes by their functions in defense mechanisms:

• B lymphocytes recognize harmful inclusions and synthesize antibodies;
• T-lymphocytes activate and inhibit immune processes, directly destroy antigens;
• NK lymphocytes perform a function control over the tissues of the native organism, are capable of killing mutated, old, degenerated cells.

Based on their size and structure, they are distinguished between large granular (NK) and small (T, B) lymphocytes. Each type of lymphocyte has its own characteristics and important functions, which are worth considering in more detail.

B lymphocytes

The distinctive features include the fact that for normal functioning the body requires not just young lymphocytes in large quantities, but hardened, mature soldiers.

Maturation and education of T cells take place in the intestines, appendix, and tonsils. In these "training camps" young bodies are trained to perform three important functions:

1. “Naive lymphocytes” are young, not activated blood cells that have no experience of encountering foreign substances, and therefore do not have strict specificity. They are able to show a limited reaction to several antigens. Activated after meeting an antigen, they are sent to the spleen or bone marrow for re-maturation and rapid cloning of their own kind. After ripening, plasma cells very quickly grow from them, producing antibodies exclusively to this type of pathogen.
2. Mature plasma cells, strictly speaking, are no longer lymphocytes, but factories for the production of specific soluble antibodies. They live only a few days, eliminating themselves as soon as the threat that caused the defensive reaction disappears. Some of them will later be “preserved” and will again become small lymphocytes with memory of the antigen.
3. Activated B-lymphocytes, with the assistance of T-lymphocytes, can become repositories of the memory of a defeated foreign agent; they live for decades, perform a function transmitting information to their “descendants”, providing long-term immunity, accelerating the body’s response to meeting the same type of aggressive influence.

B cells are very specific. Each of them is activated only when encountering a certain type of threat (a strain of a virus, a type of bacteria or protozoa, a protein, a chemical). The lymphocyte will not react to pathogens of a different nature. Thus, the main function of B lymphocytes is to provide humoral immunity and produce antibodies.

T lymphocytes

Young T-bodies are also produced by the bone marrow. This type of red blood cells undergoes the most stringent step-by-step selection, which rejects more than 90% of young cells. “Nurture” and selection occur in the thymus gland (thymus).

Note!The thymus is an organ that enters the phase of greatest development between 10 and 15 years, when its mass can reach 40 g. After 20 years, it begins to decrease. In old people, the thymus weighs like that of babies, no more than 13 g. The working tissues of the gland after 50 years are replaced by fatty and connective tissue. Accordingly, the number of T cells decreases and the body’s defenses weaken.

As a result of the selection occurring in the thymus gland, T-lymphocytes are eliminated that are not capable of binding any foreign agent, as well as those that have detected a reaction to proteins of the native organism. The remaining ripened bodies are considered suitable and are scattered throughout the body. A huge number of T cells (about 70% of all lymphocytes) circulate in the bloodstream; their concentration is high in the lymph nodes and spleen.

Three types of mature T lymphocytes leave the thymus:

• T-helpers. They help perform functions B lymphocytes, other immune agents. They guide their actions during direct contact or give orders by releasing cytokines (signal substances).
• Killer T cells. Cytotoxic lymphocytes that directly destroy defective, infected, tumor, and any modified cells. Killer T cells are also responsible for the rejection of foreign tissue upon implantation.
• T-suppressors. Execute important function supervision of the activity of B lymphocytes. Slow down or stop the immune response, if necessary. Their immediate responsibility is to prevent autoimmune reactions, when protective bodies mistake their cells for hostile ones and begin to attack them.

T-lymphocytes have the main properties: regulate the speed of the protective reaction, its duration, serve as an obligatory participant in certain transformations and provide cellular immunity.

NK lymphocytes

Unlike small forms, NK cells (null lymphocytes) are larger and contain granules consisting of substances that destroy the membrane of the infected cell or destroy it entirely. The principle of defeating hostile inclusions is similar to the corresponding mechanism in T-killers, but is more powerful and does not have pronounced specificity.

NK lymphocytes do not undergo the ripening procedure in the lymphatic system; they are able to react to any antigens and kill formations that T lymphocytes are powerless against. For such unique qualities they are called “natural killers.” NK lymphocytes are the main killers of cancer cells. Increasing their number and increasing activity is one of the promising directions for the development of oncology.

Interesting! Lymphocytes carry large molecules that transmit genetic information throughout the body. The important function of these blood cells is not limited to protection, but extends to the regulation of tissue repair, growth, and differentiation.

When necessary, null lymphocytes can function as B or T cells, thus serving as universal soldiers of the immune system.

In the complex mechanism of immune processes, lymphocytes play a leading, regulatory role. Moreover, they carry out their work both through contact and at a distance, producing special chemicals. Recognizing these command signals, all links of the immune chain are coordinated into the process and ensure the purity and durability of the human body.

agammaglobulinemia(agammaglobulinaemia; a- + gammaglobulins + Greek. haima

blood; synonym: hypogammaglobulinemia, antibody deficiency syndrome) is the general name for a group of diseases characterized by the absence or sharp decrease in the level of immunoglobulins in the blood serum; autoantigens

(auto-+ antigens) - the body’s own normal antigens, as well as antigens that arise under the influence of various biological and physicochemical factors, in relation to which autoantibodies are formed; autoimmune reaction

-- the body's immune response to autoantigens; (allergy allergy ; Greek allos other, different +

ergon action) - a state of altered reactivity of the body in the form of increased sensitivity to repeated exposure to any substances or to components of its own tissues; Allergy is based on an immune response that causes tissue damage;

The main cells that carry out immune reactions are T- and B-lymphocytes (and their derivatives - plasmacytes), macrophages, as well as a number of cells interacting with them (mast cells, eosinophils, etc.).

• Lymphocytes

The population of lymphocytes is functionally heterogeneous. There are three main types of lymphocytes:, T lymphocytes B lymphocytes and the so-called zero

There are three main types of lymphocytes: lymphocytes (0-cells). Lymphocytes develop from undifferentiated lymphoid bone marrow precursors and, upon differentiation, receive functional and morphological characteristics (presence of markers, surface receptors), detected by immunological methods. 0-lymphocytes (null) are devoid of surface markers and are considered as a reserve population of undifferentiated lymphocytes.- the most numerous population of lymphocytes, making up 70-90% of blood lymphocytes. They differentiate in the thymus gland - the thymus (hence their name), enter the blood and lymph and populate T-zones in the peripheral organs of the immune system - lymph nodes (deep part of the cortex), spleen (periarterial sheaths of lymphoid nodules), in single and multiple follicles of various organs, in which, under the influence of antigens, T-immunocytes (effector) and memory T-cells are formed. T-lymphocytes are characterized by the presence of special receptors on the plasmalemma that are capable of specifically recognizing and binding antigens. These receptors are products of immune response genes. T lymphocytes provide

cellular immunity, participate in the regulation of humoral immunity, produce cytokines under the influence of antigens. In the population of T-lymphocytes, several functional groups of cells are distinguished: cytotoxic lymphocytes (TC), or Killer T cells(Tk), T helper cells(Tx), T-suppressors(Tch).

In addition, T lymphocytes are involved in the regulation of humoral immunity with the help of Tx and Tc. Tx stimulate the differentiation of B lymphocytes, the formation of plasma cells from them and the production of immunoglobulins (Ig). Tx have surface receptors that bind to proteins on the plasmalemma of B cells and macrophages, stimulating Tx and macrophages to proliferate, produce interleukins (peptide hormones), and B cells to produce antibodies.

Thus, the main function of Tx is the recognition of foreign antigens (presented by macrophages), the secretion of interleukins that stimulate B lymphocytes and other cells to participate in immune reactions.

A decrease in the number of Tx in the blood leads to a weakening of the body’s defense reactions (these individuals are more susceptible to infections). A sharp decrease in the number of Tx in individuals infected with the AIDS virus was noted.

Tc are capable of inhibiting the activity of Tx, B-lymphocytes and plasma cells. They are involved in allergic reactions and hypersensitivity reactions. Tc suppress the differentiation of B lymphocytes.

One of the main functions of T lymphocytes is the production cytokines, which have a stimulating or inhibitory effect on cells involved in the immune response (chemotactic factors, macrophage inhibitory factor - MIF, nonspecific cytotoxic substances, etc.).

Natural killers. Among the lymphocytes in the blood, in addition to the TCs described above, which perform the function of killers, there are so-called natural killers (NK, N.K.

• ), which are also involved in cellular immunity. They form the first line of defense against foreign cells and act immediately, quickly destroying cells. NKs in their own body destroy tumor cells and cells infected with a virus. TCs form a second line of defense, since their development from inactive T lymphocytes takes time, so they come into action later than NKs. NK are large lymphocytes with a diameter of 12-15 microns, have a lobulated nucleus and azurophilic granules (lysosomes) in the cytoplasm.

The ancestor of all cells of the immune system is the hematopoietic stem cell (HSC). HSCs are localized in the embryonic period in the yolk sac, liver, and spleen. In the later period of embryogenesis, they appear in the bone marrow and continue to proliferate in postnatal life. From the BMSC, a lymphopoiesis progenitor cell (lymphoid multipotent progenitor cell) is formed in the bone marrow, which generates two types of cells: pre-T cells (precursor T cells) and pre-B cells (precursor B cells).

• T-lymphocyte differentiation

Pre-T cells migrate from the bone marrow through the blood to the central organ of the immune system - the thymus gland.

Even during embryonic development, a microenvironment is created in the thymus gland that is important for the differentiation of T lymphocytes. In the formation of the microenvironment, a special role is given to the reticuloepithelial cells of this gland, capable of producing a number of biologically active substances. Pre-T cells migrating into the thymus acquire the ability to respond to microenvironmental stimuli. Pre-T cells in the thymus proliferate and transform into T lymphocytes carrying characteristic membrane antigens (CD4+, CD8+). T-lymphocytes generate and “deliver” into the blood circulation and thymus-dependent zones of peripheral lymphoid organs 3 types of lymphocytes: Tc, Tx and Tc. “Virgin” T-lymphocytes migrating from the thymus gland (virgin T-lymphocytes) are short-lived. Specific interaction with the antigen in peripheral lymphoid organs serves as the beginning of the processes of their proliferation and differentiation into mature and long-lived cells (T-effector and memory T-cells), which make up the majority of recirculating T-lymphocytes.

Not all cells migrate from the thymus gland. Some T-lymphocytes die.. During the process of differentiation of lymphocytes, specific membrane molecules of glycoproteins appear on their surface. - Such molecules (antigens) can be detected using specific monoclonal antibodies. Monoclonal antibodies have been obtained that react with only one cell membrane antigen. Using a set of monoclonal antibodies, subpopulations of lymphocytes can be identified. There are sets of antibodies to human lymphocyte differentiation antigens. Antibodies form relatively few groups (or “clusters”), each of which recognizes a single cell surface protein. A nomenclature of differentiation antigens of human leukocytes detected by monoclonal antibodies has been created. This CD nomenclature ( CD

cluster of differentiation

- differentiation cluster) is based on groups of monoclonal antibodies that react with the same differentiation antigens.

Multiclonal antibodies to a number of differentiation antigens of human T-lymphocytes have been obtained. When determining the total population of T cells, monoclonal antibodies of CD specificities (CD2, CD3, CDS, CD6, CD7) can be used.

T-cell antigen receptors are antibody-like heterodimers consisting of α- and β-chains of polypeptides.

Each chain is 280 amino acids long, and the large extracellular portion of each chain is folded into two Ig-like domains: one variable (V) and one constant (C). The antibody-like heterodimer is encoded by genes that assemble from multiple gene segments during T cell development in the thymus.

There are antigen-independent and antigen-dependent differentiation and specialization of B and T lymphocytes. Antigen-independent

proliferation and differentiation are genetically programmed to produce cells capable of giving a specific type of immune response when encountering a specific antigen due to the appearance of special “receptors” on the plasmalemma of lymphocytes. It occurs in the central organs of the immune system (thymus, bone marrow or bursa of Fabricius in birds) under the influence of specific factors produced by cells that form the microenvironment (reticular stroma or reticuloepithelial cells in the thymus). Antigen dependent

proliferation and differentiation of T- and B-lymphocytes occur when they encounter antigens in peripheral lymphoid organs, and effector cells and memory cells (retaining information about the active antigen) are formed. The resulting T-lymphocytes form a pool long-lived , recirculating lymphocytes, and B lymphocytes - short-lived

cells.

66. Characteristics of B-lymphocytes.

B lymphocytes are the main cells involved in humoral immunity. In humans, they are formed from red bone marrow HSCs, then enter the blood and further populate the B-zones of peripheral lymphoid organs - the spleen, lymph nodes, and lymphoid follicles of many internal organs. Their blood contains 10-30% of the entire population of lymphocytes.

When exposed to an antigen, B lymphocytes in peripheral lymphoid organs are activated, proliferate, and differentiate into plasma cells that actively synthesize antibodies of various classes that enter the blood, lymph, and tissue fluid.

B cell differentiation

Precursors of B cells (pre-B cells) further develop in birds in the bursa of Fabricius (bursa), where the name B lymphocytes comes from, and in humans and mammals - in the bone marrow.

The bursa of Fabricius (bursa Fabricii) is the central organ of immunopoiesis in birds, where the development of B lymphocytes occurs, located in the cloaca. Its microscopic structure is characterized by the presence of numerous folds covered with epithelium, in which lymphoid nodules are located, bounded by a membrane. The nodules contain epithelial cells and lymphocytes at various stages of differentiation. During embryogenesis, a medullary zone is formed in the center of the follicle, and a cortical zone is formed at the periphery (outside the membrane), into which lymphocytes from the medullary zone probably migrate. Due to the fact that only B-lymphocytes are formed in the bursa of Fabricius in birds, it is a convenient object for studying the structure and immunological characteristics of this type of lymphocyte. The ultramicroscopic structure of B lymphocytes is characterized by the presence of groups of ribosomes in the form of rosettes in the cytoplasm. These cells have larger nuclei and less dense chromatin than T lymphocytes due to increased euchromatin content.

B lymphocytes differ from other cell types in their ability to synthesize immunoglobulins. Mature B lymphocytes express Ig on the cell membrane. Such membrane immunoglobulins (MIg) function as antigen-specific receptors.

Pre-B cells synthesize intracellular cytoplasmic IgM but do not have surface immunoglobulin receptors. Bone marrow virgin B lymphocytes have IgM receptors on their surface. Mature B lymphocytes carry immunoglobulin receptors of various classes on their surface - IgM, IgG, etc.

Differentiated B-lymphocytes enter the peripheral lymphoid organs, where, under the influence of antigens, proliferation and further specialization of B-lymphocytes occur with the formation of plasmacytes and memory B-cells (MB).

During their development, many B cells switch from producing antibodies of one class to producing antibodies of other classes. This process is called class switching. All B cells begin their antibody synthesis activities by producing IgM molecules, which are embedded in the plasma membrane and serve as receptors for the antigen. Then, even before interacting with the antigen, most B cells proceed to the simultaneous synthesis of IgM and IgD molecules. When a virgin B cell switches from producing membrane-bound IgM alone to simultaneously producing membrane-bound IgM and IgD, the switch probably occurs due to a change in RNA processing.

When stimulated by antigen, some of these cells become activated and begin to secrete IgM antibodies, which predominate in the primary humoral response.

Other antigen-stimulated cells switch to producing IgG, IgE, or IgA antibodies; Memory B cells carry these antibodies on their surface, and active B cells secrete them. IgG, IgE, and IgA molecules are collectively called secondary class antibodies because they appear to be formed only after antigenic stimulation and predominate in secondary humoral responses.

With the help of monoclonal antibodies, it was possible to identify certain differentiation antigens, which, even before the appearance of cytoplasmic µ-chains, make it possible to classify the lymphocyte carrying them as a B-cell line. Thus, the CD19 antigen is the earliest marker that allows a lymphocyte to be classified as a B-cell. It is present on pre-B cells in the bone marrow and on all peripheral B cells.

The antigen detected by monoclonal antibodies of the CD20 group is specific for B lymphocytes and characterizes later stages of differentiation.

On histological sections, the CD20 antigen is detected on B cells of the germinal centers of lymphoid nodules and in the cortex of the lymph nodes. B lymphocytes also carry a number of other (eg, CD24, CD37) markers.

67. Macrophages play an important role in both natural and acquired immunity of the body. The participation of macrophages in natural immunity is manifested in their ability to phagocytose and in the synthesis of a number of active substances - digestive enzymes, components of the complement system, phagocytin, lysozyme, interferon, endogenous pyrogen, etc., which are the main factors of natural immunity. Their role in acquired immunity is the passive transfer of antigen to immunocompetent cells (T and B lymphocytes) and the induction of a specific response to antigens. Macrophages are also involved in ensuring immune homeostasis by controlling the proliferation of cells characterized by a number of abnormalities (tumor cells).

For the optimal development of immune reactions under the influence of most antigens, the participation of macrophages is necessary both in the first inductive phase of immunity, when they stimulate lymphocytes, and in its final phase (productive), when they participate in the production of antibodies and the destruction of antigen. Antigens phagocytosed by macrophages induce a stronger immune response compared to those that are not phagocytosed by them. Blockade of macrophages by introducing a suspension of inert particles (for example, carcass) into the animal's body significantly weakens the immune response. Macrophages are able to phagocytose both soluble (for example, proteins) and corpuscular antigens. Corpuscular antigens cause a stronger immune response.

Some types of antigens, for example pneumococci, containing a carbohydrate component on the surface, can be phagocytosed only after preliminary opsonization. Phagocytosis is greatly facilitated if the antigenic determinants of foreign cells are opsonized, i.e. connected to an antibody or a complex of antibody and complement. The opsonization process is ensured by the presence of receptors on the macrophage membrane that bind part of the antibody molecule (Fc fragment) or part of complement (C3). Only IgG class antibodies can directly bind to the macrophage membrane in humans when they are in combination with the corresponding antigen. IgM can bind to the macrophage membrane in the presence of complement. Macrophages are able to “recognize” soluble antigens, such as hemoglobin.

There are two stages in the antigen recognition mechanism that are closely related to each other. The first stage involves phagocytosis and digestion of the antigen. In the second stage, polypeptides, soluble antigens (serum albumins) and corpuscular bacterial antigens accumulate in the phagolysosomes of the macrophage. Several introduced antigens can be found in the same phagolysosomes. The study of the immunogenicity of various subcellular fractions revealed that the most active antibody formation is caused by the introduction of lysosomes into the body. The antigen is also found in cell membranes. Most of the processed antigen material released by macrophages has a stimulating effect on the proliferation and differentiation of T- and B-lymphocyte clones. A small amount of antigenic material can persist for a long time in macrophages in the form of chemical compounds consisting of at least 5 peptides (possibly in connection with RNA).

In the B-zones of the lymph nodes and spleen there are specialized macrophages (dendritic cells), on the surface of their numerous processes many antigens are stored that enter the body and are transmitted to the corresponding clones of B-lymphocytes. In the T-zones of lymphatic follicles there are interdigitating cells that influence the differentiation of T-lymphocyte clones.

Thus, macrophages take a direct active part in the cooperative interaction of cells (T- and B-lymphocytes) in the body’s immune reactions.

The main task of T-lymphocytes is to recognize foreign or altered self-antigens as part of a complex with MHC molecules. If foreign or altered molecules are present on the surface of its cells, the T-lymphocyte triggers their destruction.

Unlike B lymphocytes, T lymphocytes do not produce soluble forms of antigen recognition molecules. Moreover, most T lymphocytes are unable to recognize and bind soluble antigens.

In order for a T-lymphocyte to “pay attention to the antigen,” other cells must somehow “pass” the antigen through themselves and display it on their membrane in complex with MHC-I or MHC-II. This is the phenomenon of antigen presentation to the T lymphocyte. Recognition of such a complex by T-lymphocytes is double recognition, or MHC restriction of T-lymphocytes.

ANTIGEN RECOGNITION T-LYMPHOCYTE RECEPTOR

T cell antigen recognition receptors, TCRs, are composed of chains belonging to the immunoglobulin superfamily (see Figure 5-1). The TCR antigen recognition region protruding above the cell surface is a heterodimer, i.e. consists of two different polypeptide chains. There are two known TCR variants, designated αβTCR and γδTCR. These variants differ in the composition of the polypeptide chains of the antigen recognition region. Each T lymphocyte expresses only 1 variant of the receptor. αβT cells were discovered earlier and studied in more detail than γδT lymphocytes. In this regard, it is more convenient to describe the structure of the antigen recognition receptor of T lymphocytes using the example of αβTCR. The transmembrane-located TCR complex consists of 8 polypeptides

Rice. 6-1. Diagram of the T cell receptor and its associated molecules

chains (a heterodimer of the α- and β-chains of the TCR itself, two auxiliary ζ chains, as well as one heterodimer each of the ε/δ- and ε/ γ-chains of the CD3 molecule) (Fig. 6-1).

. Transmembrane chainsα and β TCR. These are 2 polypeptide chains of approximately the same size -α (molecular weight 40-60 kDa, acidic glycoprotein) andβ (molecular weight 40-50 kDa, neutral or basic glycoprotein). Each of these chains contains 2 glycosylated domains in the extracellular part of the receptor, a hydrophobic (positively charged due to lysine and arginine residues) transmembrane part and a short (5-12 amino acid residues) cytoplasmic region. The extracellular parts of both chains are connected by a single disulfide bond.

- V-region. The outer extracellular (distal) domains of both chains have a variable amino acid composition. They are homologous to the V region of immunoglobulin molecules and constitute the V region of the TCR. It is the V regions of the α and β chains that interact with the MHC-peptide complex.

-C-area. The proximal domains of both chains are homologous to the constant regions of immunoglobulins; these are the C regions of the TCR.

A short cytoplasmic region (both α- and β-chains) cannot independently ensure the conduction of a signal into the cell. For this purpose, 6 additional polypeptide chains are used: γ, δ, 2ε and 2ζ.

.CD3 complex. Chainsγ, δ, ε form heterodimers among themselvesγε and δε (together they are called the CD3 complex). This complex is required for expressionα- and β-chains, their stabilization and signal transmission into the cell. This complex consists of an extracellular, transmembrane (negatively charged and therefore electrostatically associated with transmembrane regionsα- and β-chains) and cytoplasmic parts. It is important not to confuse the chains of the CD3 complex withγ δ chains of the TCR dimer.

.ζ -Chains connected to each other by a disulfide bridge. Most of these chains are located in the cytoplasm. ζ-Chains carry out the signal into the cell.

.ITAM sequences. Cytoplasmic regions of polypeptide chainsγ, δ, ε and ζ contain 10 ITAM sequences (1 sequence in eachγ-, ε- and δ-chains and 3 - in each ζ-chain), interacting with Fyn, a cytosolic tyrosine kinase, the activation of which initiates the onset of biochemical reactions to conduct a signal (see Fig. 6-1).

Antigen binding involves ionic, hydrogen, van der Waals and hydrophobic forces; the conformation of the receptor changes significantly. Theoretically, each TCR is capable of binding about 10 5 different antigens, not only related in structure (cross-reacting), but also not homologous in structure. However, in reality, TCR polyspecificity is limited to the recognition of only a few structurally similar antigenic peptides. The structural basis of this phenomenon is the feature of simultaneous TCR recognition of the MHC-peptide complex.

Coreceptor molecules CD4 and CD8

In addition to the TCR itself, each mature T lymphocyte expresses one of the so-called coreceptor molecules - CD4 or CD8, which also interact with MHC molecules on APCs or target cells. Each of them has a cytoplasmic region associated

with the tyrosine kinase Lck, and probably contributes to the transmission of the signal into the cell during antigen recognition.

.CD4(β2 domain) of the MHC-II molecule (belongs to the immunoglobulin superfamily, see Fig. 5-1, b). CD4 has a molecular weight of 55 kDa and 4 domains in the extracellular part. When a T-lymphocyte is activated, one TCR molecule is “served” by 2 CD4 molecules: dimerization of CD4 molecules probably occurs.

.CD8 associated with the invariant part(α3-domain) of the MHC-I molecule (belongs to the immunoglobulin superfamily, see Fig. 5-1, a). CD8 - chain heterodimerα and β, connected by a disulfide bond. In some cases, a homodimer of two α chains is found, which can also interact with MHC-I. In the extracellular part, each of the chains has one immunoglobulin-like domain.

T cell receptor genes

Genes α-, β-, γ- and δ-chains (Fig. 6-2, also see Fig. 5-4) are homologous to immunoglobulin genes and undergo DNA recombination during the differentiation of T-lymphocytes, which theoretically ensures the generation of about 10 16 -10 18 variants of antigen-binding receptors (in reality, this variety is limited by the number of lymphocytes in the body to 10 9).

.α-chain genes have ~54 V-segments, 61 J-segments and 1 C-segment.

.β-chain genes contain ~65 V segments, 2 D segments, 13 J segments and 2 C segments.

.δ-chain genes. Between the V- and J-segments of the α-chain are the genes of the D-(3), J-(4) and C-(1) segments of the δ-chainγ δTCR. The V segments of the δ chain are interspersed among the V segments of the α chain.

.γ-chain genes γ δTCRs have 2 C segments, 3 J segments before the first C segment and 2 J segments before the second C segment, 15 V segments.

Gene rearrangement

.DNA recombination occurs when the V-, D- and J-segments combine and is catalyzed by the same recombinase complex as during the differentiation of B lymphocytes.

.After rearrangement of VJ in α-chain genes and VDJ in β-chain genes, as well as after the addition of non-coding N- and P-nucleotides to DNA

Rice. 6-2. Genes of α- and β-chains of human T-lymphocyte antigen recognition receptor

transcribed by RNA. Fusion with the C segment and removal of excess (unused) J segments occurs during splicing of the primary transcript.

.α-chain genes can be rearranged repeatedly while β-chain genes are already correctly rearranged and expressed. This is why there is some possibility that a single cell can carry more than one TCR variant.

.TCR genes are not subject to somatic hypermutagenesis.

CONDUCTING SIGNALS FROM ANTIGEN RECOGNITION RECEPTORS OF LYMPHOCYTES

TCR and BCR have a number of common patterns of registration and transmission of activation signals into the cell (see Fig. 5-11).

. Receptor clustering. To activate a lymphocyte, clustering of antigen recognition receptors and coreceptors is necessary, i.e. “cross-linking” of several receptors with one antigen.

. Tyrosine kinases. The processes of phosphorylation/dephosphorylation of proteins at the tyrosine residue under the action of tyrosine kinases and tyrosine phosphatases play a significant role in signal transmission.

leading to the activation or inactivation of these proteins. These processes are easily reversible and “convenient” for fast and flexible cell reactions to external signals.

. Src kinases. Tyrosine-rich ITAM sequences of the cytoplasmic regions of immunoreceptors are phosphorylated by non-receptor (cytoplasmic) tyrosine kinases of the Src family (Fyn, Blk, Lyn in B lymphocytes, Lck and Fyn in T lymphocytes).

. ZAP-70 kinases(in T lymphocytes) or Syk(in B-lymphocytes), binding to phosphorylated ITAM sequences, adapter proteins are activated and begin to phosphorylate: LAT (Linker for Activation of T cells)(ZAP-70 kinase), SLP-76 (ZAP-70 kinase) or SLP-65 (Syk kinase).

. Adapter proteins recruit phosphoinositide 3-kinase(PI3K). This kinase in turn activates the serine/threonine protein kinase Akt, causing increased protein biosynthesis, which promotes accelerated cell growth.

. Phospholipase Cγ (see Fig. 4-8). Kinases of the Tec family (Btk - in B-lymphocytes, Itk - in T-lymphocytes) bind adapter proteins and activate phospholipase Cγ(PLCγ ).

PLCγ cleaves cell membrane phosphatidylinositol diphosphate (PIP 2) into inositol 1,4,5-trisphosphate (IP 3) and diacylglycerol

(DAG).

DAG remains in the membrane and activates protein kinase C (PKC), a serine/threonine kinase that activates the evolutionarily “ancient” transcription factor NFκB.

IP 3 binds to its receptor in the endoplasmic reticulum and releases calcium ions from the stores into the cytosol.

Free calcium activates calcium-binding proteins - calmodulin, which regulates the activity of a number of other proteins, and calcineurin, which dephosphorylates and thereby activates the nuclear factor of activated T-lymphocytes NFAT (Nuclear Factor of Activated T cells).

. Ras and other small G proteins in the inactive state are associated with GDP, but adapter proteins replace the latter with GTP, thereby transferring Ras to the active state.

Ras has its own GTPase activity and quickly cleaves off the third phosphate, thereby returning itself to an inactive state (self-inactivation).

In a state of short-term activation, Ras manages to activate the next cascade of kinases called MAPK (Mitogen Activated Protein Kinase), which ultimately activate the AP-1 transcription factor in the cell nucleus. In Fig. Figure 6-3 provides a schematic representation of the major TCR signaling pathways. The activation signal is turned on when the TCR binds to a ligand (MHC peptide complex) with the participation of a coreceptor (CD4 or CD8) and the co-stimulatory molecule CD28. This leads to activation of the kinases Fyn and Lck. ITAM regions in the cytoplasmic parts of CD3 polypeptide chains are marked in red. The role of Src kinases associated with the receptor in the phosphorylation of proteins: both receptor and signal ones is reflected. Noteworthy is the extremely wide range of effects of coreceptor-associated Lck kinase; the role of Fyn kinase is less certain (reflected in the discontinuous nature of the lines).

Rice. 6-3. Sources and direction of triggering activation signals during stimulation of T-lymphocytes. Designations: ZAP-70 (ζ -associated protein kinase, they say mass 70 kDa) - protein kinase p70 associated with the ζ-chain; PLCγ (Phospholipase Cγ ) - phospholipase C, isoform γ; PI3K (Phosphatidyl Inositol 3-kinase)- phosphatidylinositol 3-kinase; Lck, Fyn -tyrosine kinases; LAT, Grb, SLP, GADD, Vav - adapter proteins

The tyrosine kinase ZAP-70 plays a key role in mediating between receptor kinases and adapter molecules and enzymes. It activates (via phosphorylation) the adapter molecules SLP-76 and LAT, and the latter transmits an activation signal to other adapter proteins GADD, GRB and activates the y-isoform of phospholipase C (PLCy). Before this stage, signal transduction involves exclusively factors associated with the cell membrane. An important contribution to the activation of signaling pathways is made by the costimulatory molecule CD28, which realizes its action through the associated lipid kinase PI3K (Phosphatidyl Inositol 3-kinase). The main target of PI3K kinase is the cytoskeleton-associated factor Vav.

As a result of the formation of a signal and its transmission from the T-cell receptor to the nucleus, 3 transcription factors are formed - NFAT, AP-1 and NF-kB, which induce the expression of genes that control the process of T-lymphocyte activation (Fig. 6-4). The formation of NFAT is caused by a signaling pathway that does not depend on costimulation, which is activated due to the activation of phospholipase C and is realized with the participation of ions

Rice. 6-4. Scheme of signaling pathways during T cell activation. NFAT (Nuclear factor of activated T cells), AP-1 (Activation protein-1), NF-κB (Nuclear factor ofTo -gene of B cells)- transcription factors

Ca 2+. This pathway causes the activation of calcineurin, which, having phosphatase activity, dephosphorylates the cytosolic factor NFAT-P. Thanks to this, NFAT-P acquires the ability to migrate into the nucleus and bind to the promoters of activating genes. The AP-1 factor is formed as a heterodimer of the c-Fos and c-Jun proteins, the formation of which is induced due to the activation of the corresponding genes under the influence of factors formed as a result of the implementation of the three components of the MAP cascade. These pathways are activated by the short GTP-binding proteins Ras and Rac. A significant contribution to the implementation of the MAP cascade is made by signals dependent on costimulation through the CD28 molecule. The third transcription factor, NF-kB, is known as the main transcription factor of innate immune cells. It is activated by cleavage of the blocking IκB subunit by IKK kinase, which in T cells is activated by protein kinase C isoform ϴ (PKC9)-dependent signaling. The main contribution to the activation of this signaling pathway is made by costimulatory signals from CD28. The formed transcription factors bind to the promoter regions of genes and induce their expression. Gene expression is particularly important for the initial stages of the T cell response to stimulation IL2 And IL2R, which determines the production of T-cell growth factor IL-2 and the expression of its high-affinity receptor on T-lymphocytes. As a result, IL-2 acts as an autocrine growth factor, causing the proliferative expansion of T-cell clones involved in the response to the antigen.

DIFFERENTIATION OF T-LYMPHOCYTES

The basis for identifying the stages of T-lymphocyte development is the state of receptor V genes and TCR expression, as well as coreceptors and other membrane molecules. The differentiation scheme of T-lymphocytes (Fig. 6-5) is similar to the above scheme for the development of B-lymphocytes (see Fig. 5-13). Key characteristics of the phenotype and growth factors of developing T cells are presented. The accepted designations for the stages of T-cell development are determined by the expression of coreceptors: DN (from Double-Negative CD4CD8) - double negative, DP (from Double-Positive, CD4 + CD8 +) - double positive, SP (from Single-Positive, CD4 + CD8 - and CD4CD8 +) are single positive. The division of DNthymocytes into stages DN1, DN2, DN3 and DN4 is based on the nature

Rice. 6-5. Development of T lymphocytes

expression of CD44 and CD25 molecules. Other symbols: SCF (from Stem Cell Factor)- stem cell factor, lo (low; index mark) - low level of expression. Rearrangement stages: D-J - preliminary stage, connection of segments D and J (only in genes of the β- and δ-chains of TCR, see Fig. 6-2), V-DJ - final stage, connection of the germinal V gene with the combined segment DJ .

.Thymocytes differentiate from a common precursor cell, which, while still outside the thymus, expresses membrane markers such as CD7, CD2, CD34 and the cytoplasmic form of CD3.

.Precursor cells committed to differentiation into T lymphocytes migrate from the bone marrow to the subcapsular zone of the thymic cortex, where they slowly proliferate over approximately one week. New membrane molecules CD44 and CD25 appear on thymocytes.

.Then the cells move deeper into the thymic cortex, and the CD44 and CD25 molecules disappear from their membrane. At this stage, the rearrangement of β genes begins-, γ- and TCR δ chains. If genesγ- and δ-chains have time to be productive, i.e. without a frameshift, rearrange earlier than the β-chain genes, then the lymphocyte differentiates further asγ δT. Otherwise, the β-chain is expressed on the membrane in complex with pTα (an invariant surrogate chain that replaces the real α chain at this stage) and CD3. This serves

a signal to stop rearrangement of γ- and δ-chain genes. Cells begin to proliferate and express both CD4 and CD8 - double positive thymocytes. In this case, a mass of cells accumulates with a ready-made β-chain, but with not yet rearranged α-chain genes, which contributes to the diversity of αβ-heterodimers.

.At the next stage, the cells stop dividing and begin to rearrange Vα genes, several times over the course of 3-4 days. Rearrangement of the α-chain genes results in irreversible deletion of the δ-locus located between the segments of the α-chain genes.

.Expression of TCR occurs with each new variant of the α-chain and selection (selection) of thymocytes based on the strength of binding to the MHC-peptide complex on the membranes of thymic epithelial cells.

Positive selection: thymocytes that have not bound any of the available MHC-peptide complexes die. As a result of positive selection, about 90% of thymocytes die in the thymus.

Negative selection eliminates thymocyte clones that bind MHC-peptide complexes with too high an affinity. Negative selection eliminates from 10 to 70% of cells that have undergone positive selection.

Thymocytes that have bound any of the MHC-peptide complexes with the correct one, i.e. with average strength and affinity, they receive a signal for survival and continue differentiation.

.For a short time, both coreceptor molecules disappear from the thymocyte membrane, and then one of them is expressed: thymocytes that recognize the peptide in complex with MHC-I express the CD8 coreceptor, and with MHC-II, the CD4 coreceptor. Accordingly, two types of T-lymphocytes reach the periphery (in a ratio of about 2:1): CD8 + and CD4 +, whose functions in the upcoming immune responses are different.

-CD8+ T cells play the role of cytotoxic T-lymphocytes (CTLs) - they recognize and directly kill cells modified by the virus, tumor and other “altered” cells (Fig. 6-6).

-CD4+ T cells. The functional specialization of CD4 + T lymphocytes is more diverse. A significant part of CD4 + T-lymphocytes in the process of developing the immune response become T-helpers (helpers), interacting with B-lymphocytes, T-lymphocytes and other cells during

Rice. 6-6. The mechanism of action of a cytotoxic T-lymphocyte on a target cell. In the killer T cell, in response to an increase in Ca 2+ concentration, granules with perforin (purple ovals) and granzymes (yellow circles) merge with the cell membrane. The released perforin is incorporated into the membrane of the target cell with the subsequent formation of pores permeable to granzymes, water and ions. As a result, the target cell is lysed

direct contact or through soluble factors (cytokines). In certain cases, they can develop into CD4 + CTLs: in particular, such T lymphocytes are found in significant quantities in the skin of patients with Lyell's syndrome.

T helper subpopulations

Since the late 80s of the 20th century, it has been customary to distinguish 2 subpopulations of T helper cells (depending on what set of cytokines they produce) - Th1 and Th2. In recent years, the spectrum of CD4 + T cell subsets has continued to expand. Subpopulations such as Th17, T-regulators, Tr1, Th3, Tfh, etc. were discovered.

Major CD4+ T cell subsets:

. Th0 - CD4+ T lymphocytes in the early stages of the development of the immune response, they produce only IL-2 (a mitogen for all lymphocytes).

.Th1- differentiated subpopulation of CD4 + T-lymphocytes, specializing in the production of IFNγ, TNF β and IL-2. This subpopulation regulates many cellular immune responses, including delayed-type hypersensitivity (DTH) and CTL activation. In addition, Th1 stimulate the production of opsonizing IgG antibodies by B lymphocytes, which trigger the complement activation cascade. The development of excessive inflammation with subsequent tissue damage is directly related to the activity of the Th1 subpopulation.

.Th2- a differentiated subpopulation of CD4 + T lymphocytes specialized in the production of IL-4, IL-5, IL-6, IL-10 and IL-13. This subpopulation is involved in the activation of B lymphocytes and promotes their secretion of large quantities of antibodies of different classes, especially IgE. In addition, the Th2 subpopulation is involved in the activation of eosinophils and the development of allergic reactions.

.Th17- a subpopulation of CD4 + T lymphocytes specialized in the production of IL-17. These cells provide antifungal and antimicrobial protection of epithelial and mucosal barriers, and also play a key role in the pathology of autoimmune diseases.

.T-regulators- CD4 + T lymphocytes that suppress the activity of other cells of the immune system through the secretion of immunosuppressive cytokines - IL-10 (inhibitor of macrophage and Th1 cell activity) and TGFβ - inhibitor of lymphocyte proliferation. The inhibitory effect can also be achieved through direct intercellular interaction, since the inducers of apoptosis of activated and “spent” lymphocytes - FasL (Fas ligand) - are expressed on the membrane of some T-regulators. There are several populations of CD4 + regulatory T lymphocytes: natural (Treg), maturing in the thymus (CD4 + CD25 +, expressing the transcription factor Foxp3), and induced - localized predominantly in the mucous membranes of the digestive tract and switching to the formation of TGFβ (Th3) or IL-10 (Tr1). Normal functioning of T-regulators is necessary to maintain homeostasis of the immune system and prevent the development of autoimmune diseases.

.Additional helper populations. Recently, there has been a description of ever new populations of CD4 + T lymphocytes, classi-

classified according to the type of cytokine they predominantly produce. So, as it turned out, one of the most important populations is Tfh (from the English. follicular helper- follicular helper). This population of CD4 + T lymphocytes is predominantly located in lymphoid follicles and exerts a helper function for B lymphocytes through the production of IL-21, causing their maturation and terminal differentiation into plasma cells. In addition to IL-21, Tfh can also produce IL-6 and IL-10, which are necessary for the differentiation of B lymphocytes. Dysfunction of this population leads to the development of autoimmune diseases or immunodeficiencies. Another “newly emerging” population is Th9 - IL-9 producers. Apparently, these are Th2, which switched to the secretion of IL-9, which can cause proliferation of T helper cells in the absence of antigenic stimulation, as well as enhance the secretion of IgM, IgG and IgE by B lymphocytes.

The main subpopulations of T helper cells are presented in Fig. 6-7. The figure summarizes current ideas about adaptive subpopulations of CD4 + T cells, i.e. subpopulations forming-

Rice. 6-7. Adaptive CD4+ T cell subsets (cytokines, differentiation factors, chemokine receptors)

occurs during an immune response, and not during the natural development of cells. For all types of T helper cells, inducer cytokines are indicated (on the arrows leading to the circles symbolizing cells), transcription factors (inside the circles), chemokine receptors that direct migration (near the lines extending from the “cell surface”), and the cytokines produced ( in the rectangles to which the arrows extending from the circles are directed).

The expansion of the family of adaptive subpopulations of CD4 + T cells required a solution to the question of the nature of the cells with which these subpopulations interact (to whom they provide “help” in accordance with their helper function). These ideas are reflected in Fig. 6-8. It also provides an updated look at the functions of these subpopulations (participation in protection against certain groups of pathogens), as well as the pathological consequences of an unbalanced increase in the activity of these cells.

Rice. 6-8. Adaptive T cell subsets (partner cells, physiological and pathological effects)

γ δT lymphocytes

The vast majority (99%) of T lymphocytes undergoing lymphopoiesis in the thymus are αβT cells; less than 1% are γδT cells. The latter mostly differentiate outside the thymus, primarily in the mucous membranes of the digestive tract. In the skin, lungs, digestive and reproductive tracts, they are the dominant subpopulation of intraepithelial lymphocytes. Among all T lymphocytes in the body, γδT cells make up from 10 to 50%. In embryogenesis, γδT cells appear earlier than αβT cells.

.γδ T cells do not express CD4. The CD8 molecule is expressed on some γδT cells, but not as an ap-heterodimer, as on CD8 + apT cells, but as a homodimer of two a-chains.

.Antigen recognition properties:γδTCRs are more reminiscent of immunoglobulins than αβTCRs, i.e. capable of binding native antigens independently of classical MHC molecules - for γδT cells, preliminary processing of the antigen by APC is not necessary or not necessary at all.

.Diversityγδ TCR less than αβTCR or immunoglobulins, although in general γδT cells are able to recognize a wide range of antigens (mainly phospholipid antigens of mycobacteria, carbohydrates, heat shock proteins).

.Functionsγδ T cells have not yet been fully studied, although the prevailing opinion is that they serve as one of the connecting components between innate and acquired immunity. γδT cells are one of the first barriers to pathogens. In addition, these cells, secreting cytokines, play an important immunoregulatory role and are able to differentiate into CTLs.

NKT lymphocytes

Natural killer T cells (NKT cells) represent a special subpopulation of lymphocytes that occupy an intermediate position between innate and adaptive immune cells. These cells have features of both NK and T lymphocytes. NKT cells express αβTCR and the NK cell-specific receptor NK1.1, which belongs to the C-type lectin glycoprotein superfamily. However, the TCR receptor of NKT cells has significant differences from the TCR receptor of ordinary cells. In mice, most NKT cells express an invariant a-chain V domain, consisting of

segments Vα14-Jα18, sometimes referred to as Jα281. In humans, the V domain of the α chain consists of Vα24-JαQ segments. In mice, the α chain of the invariant TCR is predominantly complexed with Vβ8.2, and in humans, with Vβ11. Due to the structural features of the TCR chains, NKT cells are called invariant - iTCR. The development of NKT cells depends on the CD1d molecule, which is similar to MHC-I molecules. Unlike classical MHC-I molecules that present peptides to T cells, CD1d presents only glycolipids to T cells. Although the liver is thought to be the site of NKT cell development, there is strong evidence for a role for the thymus in their development. NKT cells play an important role in regulating immunity. In mice and humans with various autoimmune processes, the functional activity of NKT cells is severely impaired. There is no complete picture of the significance of such disorders in the pathogenesis of autoimmune processes. In some autoimmune processes, NKT cells can play a suppressor role.

In addition to controlling autoimmune and allergic reactions, NKT cells participate in immune surveillance, causing tumor rejection when their functional activity increases. Their role in antimicrobial protection is great, especially in the early stages of the development of the infectious process. NKT cells are involved in various inflammatory infectious processes, especially in viral liver lesions. In general, NKT cells are a multifunctional population of lymphocytes that still carry many scientific mysteries.

In Fig. 6-9 summarizes data on the differentiation of T lymphocytes into functional subpopulations. Several levels of bifurcation are presented: γ δТ/ αβТ, then for αβТ cells - NKT/ other T lymphocytes, for the latter - CD4 + /CD8 +, for CD4 + T cells - Th/Treg, for CD8 + T lymphocytes - CD8αβ/CD8αα. Differentiation transcription factors responsible for all developmental lines are also shown.

Rice. 6-9. Natural subpopulations of T-lymphocytes and their differentiation factors