Structural features of CD4 and CD8 molecules
Coreceptors belong to the immunoglobulin superfamily. Their extracellular region features characteristic V-like (variable) and C-like (constant) domains.
- The CD4 coreceptor is a single polypeptide chain with a molecular weight of approximately 56–59 kDa. Its extracellular portion consists of four alternating domains (V–C–V–C).
- The CD8 coreceptor has a dimeric structure, with chains linked non-covalently and further stabilized by disulfide bonds. Most $\alpha\beta$ T cells carry a heterodimer of $\alpha$- and $\beta$-chains (total molecular weight of 69 kDa). On certain mucosal lymphocytes, an $\alpha\alpha$ homodimer (molecular weight of 64 kDa) is expressed. Each CD8 chain contains just one V-like domain separated from the membrane by a long spacer.
| Characteristic | CD4 | CD8 |
|---|---|---|
| Structure | 1 polypeptide chain | Dimer ($\alpha\beta$ or $\alpha\alpha$) |
| Extracellular domains | Four (V–C–V–C) | One per chain (V) |
| MHC binding | MHC-II (via the $\beta_2$ domain) | MHC-I (via the $\alpha_3$ domain) |
| Main carrier cells | T helper cells, regulatory T cells | Cytotoxic T lymphocytes |
Coreceptor functions and signal transduction
Coreceptors perform three critical tasks:
- Enhancing affinity for the antigen–MHC molecule complex.
- Forming the immunological synapse.
- Intracellular signal transduction.
The cytoplasmic domains of CD4 and CD8 molecules are tightly associated with the tyrosine kinase Lck (an enzyme from the Src family). It is Lck that plays a critical role in transmitting the activation signal from the T-cell receptor. When the TCR recognizes an antigenic peptide, the coreceptor molecule undergoes a conformational change, which significantly increases the binding strength with the enzyme and triggers an intracellular cascade.
Role in immune synapse formation
Unlike the TCR–CD3 complex, coreceptor molecules initially reside within rafts—specialized, dense structural and functional microdomains of the cell membrane.
During the early stages of T-lymphocyte activation, non-covalent interaction occurs between the antigen-recognizing complex and the coreceptor. The coreceptor literally "pulls" the receptor complex into the lipid raft. As a result, an immune synapse is formed—a temporary membrane structure that ensures highly efficient antigen presentation and robust cellular activation.
Accessory molecules and suppressive effects
In addition to CD4 and CD8, other accessory molecules operate in T cells, such as CD2 (50 kDa) and CD28 (44 kDa). They also contain V- and C-like domains, and the polypeptide chains of CD28 are linked by disulfide bonds. An important difference lies in intracellular signaling: whereas CD4 and CD8 operate through the Lck kinase, the cytoplasmic tail of the CD28 molecule is associated with the PI-3K enzyme.
Interestingly, coreceptors are capable not only of activating the cell but also of transmitting suppressive (inhibitory) signals. If coreceptor molecules are artificially "cross-linked" using monoclonal antibodies, subsequent cell stimulation via the TCR leads not to activation, but to apoptosis—programmed cell death of the T lymphocyte.
The genetic paradox of receptors
Lymphocyte antigen-recognizing receptors can identify from $10^5$ to $10^6$ variants of antigenic structures. According to the classical "one gene, one protein" rule, encoding such an arsenal would require about 1 million genes.
However, the total number of genes in the human genome is less than 30,000, and by no means all of them serve the immune system. This genetic paradox is resolved through complex DNA segment rearrangement: by combining various fragments, humans express about $2.5 \times 10^7$ variants of just the V genes for the T-cell receptor.
Briefly: answers to topical questions
What intracellular proteins and signaling pathways does the Lck kinase activate after coreceptor binding?
After co-receptor binding, the tyrosine kinase Lck phosphorylates the $\zeta$-chain of the receptor complex and activates the tyrosine kinase ZAP-70.
- $\zeta$-chain — phosphorylated for subsequent binding to ZAP-70.
- ZAP-70 — upon binding to the $\zeta$-chain, it is phosphorylated by the Lck kinase, which turns on its enzymatic activity.
Further signal transmission proceeds through the LAT substrate, SLP-76 and Vav adaptor proteins, involving membrane-bound kinases, the cytoskeleton, and small G proteins.
What genetic mechanisms ensure the diversity of T-cell receptors?
The diversity of T-cell receptors is ensured through the rearrangement (recombination) of receptor genes in maturing lymphocytes. The following mechanisms are involved in this process:
- Segment combinatorial diversity — the joining of various germline V and J segments, as well as D segments for $\beta$ and $\delta$ chains.
- Junctional inaccuracy — precise or imprecise positioning of DNA strand breaks during segment rearrangement.
- Nucleotide insertion — the addition of P and N insertions at the joining sites.
- Reading frame shift — utilization of three reading frames within the D segment.
What function does the CD45 tyrosine phosphatase perform in regulating Lck kinase activity?
The CD45 protein tyrosine phosphatase functions to activate the Lck kinase by dephosphorylating it and unfolding the molecule. In the inactive state, the Lck kinase is folded due to phosphorylation of the C-terminal tyrosine residue Y505 by the Csk kinase. The CD45 molecule removes this functional block. It dephosphorylates the enzyme, making the functionally important tyrosine residue Y394 in the SH1 domain accessible for phosphorylation. Afterwards, Lck unfolds and acquires the tyrosine kinase activity required to trigger activation signals in lymphocytes.
A convenient multiplication rule for MHC binding: the product of the coreceptor number and the MHC class is always eight. CD4 interacts with MHC-II (4 × 2 = 8), and CD8 interacts with MHC-I (8 × 1 = 8).
Class and exam questions
On which cells, besides T helper cells, is the CD4 coreceptor expressed?
CD4 is also present on regulatory T cells, a subset of NKT lymphocytes, and $\gamma\delta$ T cells. Additionally, weak expression is detectable on macrophages and dendritic cells.
What is the difference between a heterodimer and a homodimer of the CD8 molecule?
The heterodimer ($\alpha\beta$) is present on most standard $\alpha\beta$ T lymphocytes. The homodimer ($\alpha\alpha$) is found predominantly on $\gamma\delta$ T cells located in mucosal membranes, although its exact physiological significance remains undetermined.
Which kinase is associated with the CD28 molecule?
Unlike CD4 and CD8, which transmit signals via the Lck tyrosine kinase, the cytoplasmic tail of the CD28 molecule is linked to the PI-3K enzyme.
What else to study on this topic
- Mechanisms of genetic recombination of TCR V genes
- Structure and functions of the Lck tyrosine kinase
- Features of cell membrane lipid rafts
- Mechanisms of apoptosis triggering during coreceptor cross-linking
- Specifics of antigen recognition in $\gamma\delta$ T cells
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