Receptor variants and cellular subpopulations
T lymphocytes are characterized by a strict single-receptor rule: each cell carries only one type of antigen-recognizing dimer on its membrane — either $\alpha\beta$ or $\gamma\delta$.
- $\alpha\beta$ TCR. This is the primary receptor type. Lymphocytes bearing this TCR comprise over 95% of the total T-cell pool. They freely circulate in the blood and lymph and are also localized in secondary lymphoid organs.
- $\gamma\delta$ TCR. The second receptor variant, discovered by the late 1980s. This is a minor subpopulation comprising only 1–3%. However, $\gamma\delta$ T cells exhibit a marked tropism for barrier tissues. For example, in the intestinal mucosa, their content can reach 20–30% of all local T lymphocytes.
Molecular organization of recognition dimers
The antigen-recognizing part of the receptor belongs to the immunoglobulin superfamily. However, the TCR molecule is structured much more simply than classical antibodies and bears more similarity to immunoglobulin light (L) chains. Soluble forms of TCR are not normally formed—these are exclusively membrane proteins.
Each of the two polypeptide chains in the dimer has a molecular weight of 40–60 kDa and consists of the following regions:
- Short cytoplasmic region (3–5 amino acid residues).
- Transmembrane region (10–12 residues).
- Extracellular domains (containing 87–113 amino acids). Each chain has two—a constant (C) domain, located closer to the membrane, and a variable (V) domain, distal. Both domains are formed by $\beta$-sheets and have one glycosylation site each.
The polypeptide chains are connected to each other by a disulfide bond in the hinge region above the membrane. Electrostatic forces provide additional stability to the complex: the transmembrane fragments of the chains carry opposite charges.
Recognition features Interaction with the antigen occurs in the region of V domains, which include 4 relatively stable framework regions and 3 hypervariable regions (CDRs). The hypervariable regions of both chains together form the antigen-binding cavity. The recognition mechanism is strictly distributed: the most variable CDR3 contacts the antigenic peptide directly, whereas CDR1 and CDR2 bind to adjacent regions of the MHC molecule.
Signaling apparatus: CD3 complex and $\zeta$ chains
Because the intracellular tails of $\alpha\beta$ and $\gamma\delta$ dimers are too short, they cannot transmit a signal into the cell. This function is performed by the non-covalently associated CD3 complex, which consists of $\gamma$, $\delta$, and $\varepsilon$ polypeptide chains.
At the center of the receptor complex lies a dimer of $\zeta$ chains (now classified as a separate marker, CD247). The $\zeta$ chain is unique in its structure:
- It does not belong to the immunoglobulin superfamily and lacks glycosylation sites.
- Of the chain's 143 amino acids, the vast majority (112 residues) form a long intracellular tail.
The cytoplasmic portion of each CD3 chain contains one ITAM activation motif, while each $\zeta$ chain contains three such motifs. Key intracellular tyrosine kinases attach specifically to these sites: the Fyn enzyme is associated with CD3, and the ZAP-70 kinase transmits the signal from the $\zeta$ dimer.
CD4 and CD8 coreceptors
For full lymphocyte activation, a TCR alone is not enough. Coreceptors are essential in recognizing the antigen+MHC complex, increasing the affinity of the receptor apparatus for the ligand by approximately 100-fold. Their cytoplasmic regions are associated with the Lck kinase.
Coreceptors operate under a strict restriction rule:
- CD8 (a dimeric molecule) is expressed on cytotoxic T lymphocytes and interacts only with MHC class I molecules.
- CD4 (a monomer of 4 domains) is a marker of T helper cells and binds exclusively to MHC class II.
Clinical fact: the V1 outer domain of the CD4 coreceptor not only is responsible for interacting with MHC-II, but is also the main target for the HIV-1 virus, providing it with a receptor site (amino acid residues 31–57 and 81–94) for cell entry.
Briefly: answers to topical questions
What functions do CD4 and CD8 coreceptors perform during T-lymphocyte activation?
CD4 and CD8 coreceptors participate in the recognition of the "antigenic peptide + MHC molecule" complex together with the main T-cell receptor. They perform the following functions:
- Affinity enhancement — increase the affinity of the receptor complex for the antigenic complex 100-fold due to additional binding to MHC molecules (CD4 binds to MHC-II, and CD8 to MHC-I).
- Signal transduction — their cytoplasmic tails are associated with the intracellular tyrosine kinase Lck, which is necessary for activation.
- Synapse formation — CD4 forms a non-covalent bond with the TCR and "pulls" the receptor into the lipid raft, ensuring its incorporation into the immune synapse.
What intracellular signaling pathways are activated after phosphorylation of the ITAM motifs of the T-cell receptor?
Following the phosphorylation of ITAM motifs, the ZAP-70 tyrosine kinase binds to them and becomes activated, which then phosphorylates the LAT adaptor protein. Phosphorylated LAT binds signaling molecules, including SLP-76, Grb2, Vav, PLCγ1, and PI3K.
As a result, the following links of the signaling cascade are activated:
- Calcineurin pathway — IP3 promotes the release of Ca2+ from the endoplasmic reticulum; Ca2+ activates calcineurin, which dephosphorylates NF-AT and ensures its translocation into the nucleus.
- PLCγ1 pathway — phospholipase Cγ1 is involved in the signaling cascade.
- PI3K pathway — phosphoinositide 3-kinase is involved in the signaling cascade.
Transcription factors NF-κB, AP-1, and NFAT are activated, which is accompanied by the expression of genes required for proliferation and differentiation, including IL-2 and CD25.
Which genes encode the alpha and beta chains of the T-cell receptor, and on which chromosomes are they located?
The alpha and beta chains of the T-cell receptor are encoded by segmented loci located on different chromosomes.
- Alpha-chain gene (TRAV) — located on chromosome 14 (locus 14q). The locus contains L, V, D, J, and C gene segments (and also includes delta-chain genes).
- Beta-chain gene (TRBV) — located on chromosome 7 (locus 7q). The locus contains L, V, D, J, and C gene segments.
Which enzymes carry out the V(D)J recombination process during T-cell receptor maturation?
The V(D)J recombination process during T-cell receptor maturation includes the following components:
- RAG-1 and RAG-2 — recombinases that form an active complex which binds to DNA and introduces a break at the boundary of gene segments.
- Endonuclease — introduces an asymmetric single-strand break into the generated DNA "hairpin".
- Terminal deoxynucleotidyl transferase (TdT) — performs non-template synthesis of oligodeoxynucleotides.
- DNA-dependent protein kinase.
- DNA ligase IV.
Also, heterodimers HMG1/2 and Ku70/Ku80 participate in the complex.
The restriction rule is easy to remember mathematically: the product of the coreceptor digit and the MHC class must always equal eight. CD4 interacts with MHC-II (4 × 2 = 8), and CD8 interacts with MHC-I (8 × 1 = 8).
Class and exam questions
Does the CD3 complex participate in antigen recognition?
No, CD3 molecules are incapable of recognizing antigens. Their sole, yet critically important function is to transmit a chemical signal inside the lymphocyte after the TCR has bound to the ligand.
Where does the assembly of the T-cell receptor take place?
Assembly starts in the endoplasmic reticulum, where the CD3 tetramer is formed and the antigen-specific dimer is attached. Then the complex undergoes glycosylation in the Golgi apparatus and is translocated to the membrane.
Can the CD3 complex be expressed on the membrane without the TCR?
This is clinically impossible. Without the incorporation of the antigen-specific dimer ($\alpha\beta$ or $\gamma\delta$), the free CD3 complex degrades or remains trapped in the cell cytoplasm.
What else to study on this topic
- Spatial models of the quaternary structure of TCR-CD3
- Mechanism of interaction of $\beta$-chains with superantigens
- Genetic diversity of TCR V-domain families
- Structural features of the $\zeta$-dimer in mucosal T cells
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