T cell receptor (TCR). On the surface of effector, immune T-lymphocytes there are T-cell receptors for antigen, which are structurally reminiscent of antibodies. The T-cell receptor is a heterodimer and consists of alpha and beta (molecular weight 40-50 kOa) and, less often, of β/β chains (1-5% of cells in the blood). T-lymphocytes with?/? predominate in the intestinal epithelium and skin. receptors. They recognize mycobacterial antigens and interact with the heat shock protein p65. Each chain has variable and constant regions-domains, similar to those found in immunoglobulins. Given this similarity, TCRs are classified as members of the immunoglobulin receptor superfamily.
The variable domains of the chains form a structure that ensures antigen recognition. TCR is tightly bound to the CD3 complex, consisting of 5 polypeptide chains (gamma, delta, epsilon, zeta, theta) which transmits the signal from the receptor into the cell. Therefore, the entire TKP-CD3 structure functions as a seven-peptide complex. T cell receptor variants pre-exist for each antigen. This diversity of receptors is genetically programmed (in embryos, there are 30-500 genes that control variable chain domains). However, the number of genes encoding T-receptors and antibodies is small - about 1000. Genes located on chromosome 14 are responsible for the synthesis of the β-chain, and the synthesis of the β-chain is determined by the V, D, J minigene loci. Between them, as in immunoglobulin genes, recombinations and associations are observed, which create different variants of receptors for many antigens. Recombinations of variable chain genes lead to the appearance of about 3000 variants of a and 1000 variants of b chains and only 40? and 27?. Their various associations create more than 4 million TKR2 variants and 10,000 TKR1 antigen-specific T cell receptors. The antigen binds to those receptors that best correspond to it and stimulates the division of the corresponding cells. These cells form a large clone. Helper T cells interact with antigen associated with their own MHC class II molecules, and suppressor T cells recognize the antigen in combination with MHC class I molecules. Moreover, the antigen must be presented in the form of a peptide with a length of 9-11 amino acids for T-suppressors and 12-25 for T-helpers, i.e., digested by antigen-presenting cells. TCR does not interact with ordinary proteins, polysaccharides, or lipids.
Effector lymphocytes of different subpopulations are distinguished big number various mediators. In addition to interleukins, these are lymphokines - chemotaxis factors, factors that suppress the migration of granulocytes and macrophages, mitogenic factors, etc.
Associated with molecules of the major histocompatibility complex (eng. MHC) on the surface of antigen-presenting cells. The TCR consists of two subunits anchored in the cell membrane and associated with the multisubunit CD3 complex. The interaction of the TCR with the MHC and its associated antigen leads to the activation of T lymphocytes and is a key point in triggering the immune response.
Structure
TCR is a heterodimeric protein consisting of two subunits - α and β or γ and δ, presented on the cell surface. The subunits are anchored in the membrane and linked to each other by disulfide bonds.
By their structure, TCR subunits belong to the immunoglobulin superfamily. Each of the subunits is formed by two domains with a characteristic immunoglobulin fold, a transmembrane segment and a short cytoplasmic region.
The N-terminal domains are variable (V) and are responsible for binding antigen presented by molecules of the major histocompatibility complex. The variable domain contains a hypervariable region (CDR) characteristic of immunoglobulins. Due to the extraordinary diversity of these areas, different T cells are able to recognize a wide range of different antigens.
The second domain is constant (C) and its structure is the same in all subunits of this type in a specific individual (with the exception of somatic mutations at the level of genes for any other proteins). In the region between the C domain and the transmembrane segment there is a cysteine residue, with the help of which a disulfide bond is formed between the two TCR chains.
TCR subunits are aggregated with the membrane polypeptide complex CD3. CD3 is formed by four types of polypeptides - γ, δ, ε and ζ. Subunits γ, δ and ε are encoded by closely linked genes and have a similar structure. Each of them is formed by one constant immunoglobulin domain, a transmembrane segment and a long (up to 40 amino acid residues) cytoplasmic part. The ζ chain has a small extracellular domain, a transmembrane segment, and a large cytoplasmic domain. Sometimes, instead of the ζ chain, the complex includes the η chain - a longer product of the same gene, obtained by alternative splicing.
Since the structure of the proteins of the CD3 complex is invariant (does not have variable regions), they are not able to determine the specificity of the receptor to the antigen. Recognition is solely a function of the TCR, and CD3 mediates signal transmission into the cell.
The transmembrane segment of each CD3 subunit contains a negatively charged amino acid residue, and the TCR is positively charged. Due to electrostatic interactions, they are combined into a common functional complex of the T-cell receptor. Based on stoichiometric studies and measurements of the molecular weight of the complex, its most likely composition is (αβ) 2 +γ+δ+ε 2 +ζ 2 .
TCRs consisting of αβ chains and γδ chains are very similar in structure. These forms of receptors are presented differently in different tissues of the body.
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Excerpt characterizing the T-cell receptor
- All the Cossacks struck. They cleaned the hut for the colonel and took them out. It’s a pity to watch, guys,” said the dancer. - They tore them apart: so the living one, believe it, babbles something in his own way.“They’re pure people, guys,” said the first. - White, just like a birch is white, and there are brave ones, say, noble ones.
- How do you think? He has recruited from all ranks.
“But they don’t know anything our way,” the dancer said with a smile of bewilderment. “I say to him: “Whose crown?”, and he babbles his own. Wonderful people!
“It’s strange, my brothers,” continued the one who was amazed at their whiteness, “the men near Mozhaisk said how they began to remove the beaten, where the guards were, so after all, he says, theirs lay dead for almost a month.” Well, he says, it lies there, he says, theirs is how the paper is white, clean, and doesn’t smell of gunpowder.
- Well, from the cold, or what? - one asked.
- You're so smart! By cold! It was hot. If only for the cold, ours wouldn’t have gone rotten either. Otherwise, he says, when you come up to ours, he’s all rotten with worms, he says. So, he says, we’ll tie ourselves with scarves, and, turning our muzzle away, we’ll drag him; no urine. And theirs, he says, is as white as paper; There is no smell of gunpowder.
Everyone was silent.
“It must be from the food,” said the sergeant major, “they ate the master’s food.”
Nobody objected.
“This man said, near Mozhaisk, where there was a guard, they were driven away from ten villages, they carried them twenty days, they didn’t bring them all, they were dead. What are these wolves, he says...
“That guard was real,” said the old soldier. - There was only something to remember; and then everything after that... So, it’s just torment for the people.
- And that, uncle. The day before yesterday we came running, so where they won’t let us get to them. They quickly abandoned the guns. On your knees. Sorry, he says. So, just one example. They said that Platov took Polion himself twice. Doesn't know the words. He’ll take it: he’ll pretend to be a bird in his hands, fly away, and fly away. And there is no provision for killing either.
“It’s okay to lie, Kiselev, I’ll look at you.”
- What a lie, the truth is true.
“If it were my custom, I would have caught him and buried him in the ground.” Yes, with an aspen stake. And what he ruined for the people.
“We’ll do it all, he won’t walk,” said the old soldier, yawning.
The conversation fell silent, the soldiers began to pack up.
- See, the stars, passion, are burning! “Tell me, the women have laid out the canvases,” said the soldier, admiring the Milky Way.
- This, guys, is for a good year.
“We’ll still need some wood.”
“You’ll warm your back, but your belly is frozen.” What a miracle.
- Oh my God!
- Why are you pushing, is the fire about you alone, or what? See... it fell apart.
From behind the established silence, the snoring of some who had fallen asleep was heard; the rest turned and warmed themselves, occasionally talking to each other. A friendly, cheerful laugh was heard from the distant fire, about a hundred paces away.
“Look, they’re roaring in the fifth company,” said one soldier. – And what a passion for the people!
One soldier got up and went to the fifth company.
“It’s laughter,” he said, returning. - Two guards have arrived. One is completely frozen, and the other is so courageous, dammit! Songs are playing.
- Oh oh? go have a look... - Several soldiers headed towards the fifth company.
The fifth company stood near the forest itself. A huge fire burned brightly in the middle of the snow, illuminating the tree branches weighed down with frost.
In the middle of the night, soldiers of the fifth company heard footsteps in the snow and the crunching of branches in the forest.
“Guys, it’s a witch,” said one soldier. Everyone raised their heads, listened, and out of the forest, into the bright light of the fire, two strangely dressed human figures stepped out, holding each other.
These were two Frenchmen hiding in the forest. Hoarsely saying something in a language incomprehensible to the soldiers, they approached the fire. One was taller, wearing an officer's hat, and seemed completely weakened. Approaching the fire, he wanted to sit down, but fell to the ground. The other, small, stocky soldier with a scarf tied around his cheeks, was stronger. He raised his comrade and, pointing to his mouth, said something. The soldiers surrounded the French, laid out an overcoat for the sick man, and brought porridge and vodka to both of them.
T-cell receptors (TCR) are surface protein complexes of T-lymphocytes responsible for recognizing processed antigens associated with molecules of the major histocompatibility complex (MHC) on the surface of antigen-presenting cells. The TCR consists of two subunits anchored in the cell membrane and associated with the multisubunit CD3 complex. The interaction of the TCR with the MHC and its associated antigen leads to the activation of T lymphocytes and is a key point in triggering the immune response.
TCR is a heterodimeric protein consisting of two subunits - α and β or γ and δ, presented on the cell surface. The subunits are anchored in the membrane and linked to each other by disulfide bonds.
By their structure, TCR subunits belong to the immunoglobulin superfamily. Each of the subunits is formed by two domains with a characteristic immunoglobulin fold, a transmembrane segment and a short cytoplasmic region.
The N-terminal domains are variable (V) and are responsible for binding antigen presented by molecules of the major histocompatibility complex. The variable domain contains a hypervariable region (CDR) characteristic of immunoglobulins. Due to the extraordinary diversity of these areas, different T cells are able to recognize a wide range of different antigens.
The second domain is constant (C) and its structure is the same in all subunits of this type in a particular individual (with the exception of somatic mutations at the level of the genes of any other proteins). In the area between the C domain and the transmembrane segment there is a cysteine residue, which forms a disulfide bond between the two TCR chains.
TCR subunits are aggregated with the membrane polypeptide complex CD3. CD3 is formed by four types of polypeptides - γ, δ, ε and ζ. Subunits γ, δ and ε are encoded by closely linked genes and have a similar structure. Each of them is formed by one constant immunoglobulin domain, a transmembrane segment and a long (up to 40 amino acid residues) cytoplasmic part. The ζ chain has a small extracellular domain, a transmembrane segment, and a large cytoplasmic domain. Sometimes, instead of the ζ chain, the complex includes the η chain, a longer product of the same gene obtained by alternative splicing.
Since the structure of the proteins of the CD3 complex is invariant (does not have variable regions), they are not able to determine the specificity of the receptor to the antigen. Recognition is solely a function of the TCR, and CD3 mediates signal transmission into the cell.
The transmembrane segment of each CD3 subunit contains a negatively charged amino acid residue, while the TCR contains a positively charged one. Due to electrostatic interactions, they are combined into a common functional complex of the T-cell receptor. Based on stoichiometric studies and molecular weight measurements of the complex, its most likely composition is (αβ)2+γ+δ+ε2+ζ2.
TCRs consisting of αβ chains and γδ chains are very similar in structure. These forms of receptors are presented differently in different tissues of the body.
The structure of the T-lymphocyte receptor is in many ways similar to the structure of the antibody molecule. T-cell receptor (TCR) molecules consist of two chains - a and p. Each of them contains V- and C-domains, their structure is fixed by disulfide bonds. The variable domains of the a- and p-chains have not 3-4, as in antibodies, but at least 7 hypervariable regions, which form the active center of the receptor. Behind the C domains, near the membrane, there is a hinge region of 20 amino acid residues. It provides the connection of a- and p-chains using disulfide bonds. Behind the hinge region is a transmembrane hydrophobic domain of 22 amino acid residues, which is associated with a short intracytoplasmic domain of 5-16 amino acid residues. Recognition of the presented antigen by the T-cell receptor occurs as follows. MHC class P molecules, like T-lymphocyte receptors, consist of two polypeptide chains - a and p. Their active site for binding the presented antigenic peptides is shaped like a “cleft.” It is formed by helical sections of the a- and p-chains, connected at the bottom of the “gap” by a non-helical region formed by segments of one and the other chain. At this center (cleft), the MHC molecule attaches the processed antigen and thus presents it to T cells (Fig. 63). The active center of the T-cell receptor is formed by the hypervariable regions of the a- and p-chains. It also represents a kind of “gap”, the structure of which corresponds to the spatial structure of the peptide fragment of the antigen represented by the MHC class P molecule to the same extent as the structure of the active center of the antibody molecule corresponds to the spatial structure of the antigen determinant. Each T-lymphocyte carries receptors for only one peptide, that is, it is specific for a specific antigen and binds only one type of processed peptide. The attachment of the presented antigen to the T-cell receptor induces the transmission of a signal from it to the cell genome.
For any TCR to function, it requires contact with the CD3 molecule. It consists of 5 subunits, each of which is encoded by its own gene. All subclasses of T lymphocytes have CD3 molecules. Thanks to the interaction of the T-cell receptor with the CD3 molecule, the following processes are ensured: a) removal of TCR to the surface of the T-lymphocyte membrane; b) imparting an appropriate spatial structure to the T-cell receptor molecule; c) reception and transmission of a signal by the T-cell receptor after its contact with the antigen into the cytoplasm, and then into the genome of the T-lymphocyte through the phosphatidylinositol cascade with the participation of intermediaries.
As a result of the interaction of the MHC class P molecule carrying the antigenic peptide with the T-lymphocyte receptor, the peptide is inserted into the “gap” of the receptor, which is formed by the hypervariable regions of the a- and p-chains, while contacting both chains
Table of contents of the topic "CD8 lymphocytes. Antigen (Ag) representing cells. Classification of antigens (Ag).":T cell receptor. T cells recognize Ag using two types of membrane glycoproteins - T cell receptors and CD3. The T-cell receptor is a heterodimer containing a- and p-chains (about 98% of all T cells) or 5-chains (about 1.5-2% of cells) with a molecular weight of 40-50 kDa. The T-cell receptor is a member of the superfamily of Ig-like cell surface molecules involved in recognition reactions. The mechanisms of transmembrane transmission from the T cell receptor remain unknown; they are presumably caused by CD3 non-covalently associated with T-lymphocyte receptors.
T cell activation
To activate T cells two signals from macrophages are required. The first signal is the presentation of Ag, the second is the secretion of activating factor (IL-1). The latter stimulates the synthesis of IL-2 by T lymphocytes, which activates these cells (autocrine regulation). At the same time, the expression of receptors for IL-2 (CD25) increases on the membranes of T cells.
Subpopulations of T lymphocytes
Based on surface markers, several are distinguished subpopulations of T lymphocytes, performing various functions. For T cell differentiation use a set of monoclonal ATs that detect surface marker CD-Ags [from English. cluster of differentiation, cluster of differentiation]. All mature T cells express surface CD3 Ag; In addition to it, subpopulations of T lymphocytes also express other CD Ags.
CD4 + lymphocytes
CD4 membrane molecules carry different populations of cells, conditionally divided into regulatory (helpers) and effector (T gzt).
T helper cells[from English to help, help] specifically recognize Ag and interact with macrophages and B cells during the induction of a humoral immune response. The CD4 + /CD8 + cell ratio is an important parameter for assessing immune status; Under normal conditions, the CD4 + /CD8 + ratio is approximately two and reflects the dominant influence of stimulating factors on the immune response. In some immunodeficiency states, the ratio is reversed (less than I, that is, CD8 + cells dominate), indicating a predominant influence of immunosuppressive effects; underlies the pathogenesis of many immunodeficiencies (for example, AIDS).
Ag recognizing T lymphocytes“recognize” a foreign epitope of a viral or tumor Ag in complex with an MHC molecule on the plasma membrane of the target cell. T-HRT [T-effectors of delayed-type hypersensitivity reactions (DTH)] mediate DTH reactions.
The organization of the genes encoding the a- and 3-chains of TCRs is basically homologous to that known for the light and heavy chains of immunoglobulins. The V domain of the a-chain, like the light chain of immunoglobulins, is controlled only by the V and J gene segments. B At the same time, the formation of the V-domain (3-chain, like the heavy chain of immunoglobulins, is ensured by a full set of V-, D-, J- gene segments (Fig. 3.14).
There are more than 100 V genes for the α chain in the T cell genome
TCR, which is two and a half times less than the amount known for the light chains of immunoglobulins. Each such gene includes two exons - one for the leader (L) sequence, which is absent in the mature a-chain, but is present in this chain at the time of its transport from the endoplasmic reticulum to the cell surface, and the second for encoding the TCR V domain itself. There are significantly more J-Gene segments for the a-chain than for the light chain of immunoglobulins (50 versus 4). The constant region of the a-chain is controlled by the C gene, which includes separate exons for the C-domain, hinge, and one common exon for the transmembrane and tail parts of the molecule.
The number of V genes for the 3-chain is 30. In addition, there are two DJC clusters. Each cluster includes one D and six J gene segments. Functional differences between the clusters are unknown. The C gene for the constant region of the 3-chain includes four exons for the constant, hinge, transmembrane and tail regions of the polypeptide.
The processes of recombination, transcription, splicing and translation of genetic material for the α- and β-chains during the formation of TCR in T cells are similar to those that ensure the synthesis of immunoglobulins in B cells.
As in the case of immunoglobulins and immunoglobulin receptors, TCR variability depends on the random interaction of gene segments during the recombination of genetic material encoding V-domains: VJ - for i-chains and VDJ - for (3-chains. Calculation of variability of V-domains TCR, which is carried out in the same way as for immunoglobulins (see Chap.
- , shows extremely high level diversity of these anti-
At the first stage of work, a total, undifferentiated population of T cells containing a variety of clones was obtained from mice immunized with a specific antigen (AG) (numbers 1-6 in Fig.). The second stage consisted of isolating individual clones of T cells, among which were those specific to the antigen used (the figure shows four clones as an example, one of which, clone 3, specifically reacts with the antigen). The third stage of work included the production of monoclonal antibodies (mAbs) to the antigen-reactive clone. The goal of this stage is to obtain monoclonal antibodies that can react only with the clone used for immunization. At the same time, the cross-reaction of mAbs indicates the general specificity of the antigen-reactive clone and unprimed clones (top table). The absence of mAb cross-reactivity indicates the presence of a special specificity in the positively reacting primed clone, presumably an antigen recognition receptor. This assumption is confirmed by the reaction of delayed interaction of the mAb with the corresponding clone in the presence of the antigen used (lower table). The production of mAb to the antigen recognition receptor of T cells created the conditions for its full study
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T-cell antigen recognition receptor (TCR) is a heterodimer composed of a- and p-chains. Each chain includes two domains: variable (V) and constant (C). The interacting Va and Ur domains form the antigen recognition region of the TCR. In addition to the main V- and C-domains, the TCR structure has a hinge region with a cysteine residue that forms a covalent bond between the a- and p-chains, as well as a transmembrane and short tail region
gene recognition structures (Table 3.2). Given the general similarity in the organization and recombination of genetic material for immunoglobulins and TCRs, some features in controlling the specificity of these molecules should also be noted.
Immunoglobulins and immunoglobulin receptors 6-cells recognize native antigenic epitopes. In this regard, individual areas of the antigen recognition center have an equal chance of variability. The situation with TCR is somewhat different, since this receptor recognizes the complex of the antigenic peptide with MHC molecules.
TCR diversity is largely associated with the third loop V-domain a, formed by the third hypervariable region - CDR3 (abbreviated from English, “complementarity determining region”). When an antigen-binding center is formed by the V domains of the a- and 0-chains, CDR3 ends up in the inner part of this center. The first and second loops (CDR1 and CDR2, respectively) occupy the periphery of the center. In such a conformational structure
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Rice. 3.14. Ortshnzatsp geoon, controlling a- and p-tsesh T-isshyugo retsytgots.
The principle of reorganization of the gene segments that control a- and p-cspi TCRs is the same as for immunoglobulins. The difference is that the locus for (3-strand) has two identical clusters. The functional significance of this duplication is unknown
Table 3.2
Variability of T-cell receptors in comparison with
immunoglobulin receptors and immunoglobulins 
There is a very definite biological meaning associated with the adaptation of TCR to the form of the antigen with which it interacts. As already noted, antigenic peptides fill the space (gap) formed by the α-helical structures of MHC molecules and thus find themselves in the middle of the peptide-MHC antigenic complex. Such a complex is characterized by a huge variety of antigenic specificities associated with peptides and a limited diversity characteristic of MHC molecules. Due to this organization of the immunogenic complex, one would expect increased variability in CDR3 and less variability in CDR1 and CDR2. The study of the genetic organization of genes for TCR confirms this point of view. Thus, TCR has a significantly smaller number of V genes, which determine the specificity of CDR1 and CDR2, compared to immunoglobulins, but at the same time an increased number of J segments involved in coding CDR3 (see Table 3.2). In Fig. Figure 3.15 presents a simplified diagram illustrating the interaction of COY with a peptide and CDR1 and CDR2 with the α-helical sequence of MHC molecules.