Initiation of the Response: The Two-Signal Model
The activation process begins with direct physical contact between an antigen-presenting cell (APC) and a T-cell. To ensure an appropriate immune response, nature employs a stringent control mechanism known as the "two-signal model." For a T-cell to become fully activated, exactly two signals must be delivered simultaneously.
- Primary signal. This signal is responsible for specific pathogen recognition. The major histocompatibility complex (MHC) on the APC surface interacts directly with the CD3 receptor complex on the T-cell membrane.
- Co-stimulatory signal. This is a confirmatory signal required for cell activation. It occurs via co-receptor complex formation. CD80 or CD86 molecules on the APC must bind to the CD28 receptor on the T-cell surface.
Only when both conditions are met—both the primary and co-stimulatory signals—does the T-cell proceed to the next stage of activation.
Intracellular Signal Transduction
Once the two-signal model requirements are successfully met at the membrane, the signal is transmitted inside the T-cell. A strict cascade of biochemical reactions known as the calcineurin pathway is triggered in the cytoplasm.
The initial steps of this intracellular pathway are as follows:
- First, the intracellular domain of the CD3 protein located in the T-cell cytoplasm is activated.
- This event leads to a sharp increase in intracellular calcium ($Ca^{2+}$) levels.
- Calcium ions act as secondary messengers, activating a specific $Ca^{2+}$-binding protein: calcineurin (CaN).
- Biochemically, calcineurin functions as a phosphatase enzyme. Its primary task at this stage is to act on the nuclear factor of activated T-cells (NFAT).
- Under the influence of calcineurin, NFAT is converted from its initial inactive form (NFAT-) to its active state (NFAT+). This transition triggers further profound activation of the lymphocyte.
Pharmacologic Targets and Drugs
A detailed understanding of intercellular interactions and intracellular signaling has enabled the development of drugs capable of modulating the immune response. Pharmacology identifies two key targets for blocking early T-cell activation.
The first target is the CD3 receptor, which is responsible for initiating the primary signal. The drug muromonab-CD3 specifically binds to this receptor on the T-cell surface. By blocking the receptor, the drug prevents antigen recognition and makes contact with the APC's MHC complex impossible.
The second target is located inside the cell: the enzyme calcineurin. Well-known drugs such as cyclosporine and tacrolimus penetrate the cytoplasm and selectively inhibit calcineurin (CaN). As a result, the activation of the NFAT nuclear factor is blocked. The signaling cascade is interrupted at a very early stage, and the T-cell remains inactive even if primary contact with the antigen-presenting cell has already occurred.