T-Lymphocyte Activation

Response initiation: two-signal model

The activation process begins with direct physical contact between two cells: the antigen-presenting cell (APC) and the T lymphocyte itself. For the immune system to respond adequately, nature has provided a strict control mechanism known as the "two-signal model". For the T lymphocyte to fully function, the simultaneous presence of exactly two signals is required.

1. Primary signal. It is responsible for specific recognition of a threat. The major histocompatibility complex (MHC) is located on the surface of the antigen-presenting cell. It enters into direct interaction with the CD3 receptor complex located on the T-lymphocyte membrane.
2. Co-stimulatory signal. This is a confirming signal, without which the cell is not activated. It arises through the formation of a co-receptor complex. CD80 or CD86 molecules presented on the APC surface must bind to the specific CD28 receptor on the T-lymphocyte surface.

Only when both conditions are met—the presence of both the primary and co-stimulatory signals—does the T lymphocyte proceed to the next stage of activation.

Intracellular signaling

Upon successful fulfillment of the two-signal model conditions on the membrane, the signal is transmitted into the T lymphocyte. A strict chain of biochemical reactions, known as the calcineurin cascade, is triggered in the cytoplasm.

The initial stages of this intracellular pathway are as follows:

• First, activation of the intracellular part of the CD3 protein located in the lymphocyte cytoplasm occurs.
• This event leads to a sharp increase in the level of intracellular calcium ($Ca^{2+}$).
• Calcium ions act as secondary messengers and activate a specific $Ca^{2+}$-binding protein — calcineurin (CaN).
• In its biochemical function, calcineurin is a phosphatase enzyme. Its main task at this stage is to act on the nuclear factor of activated T cells (NFAT).
• Under the action of calcineurin, the NFAT factor is converted from its initial inactive form (NFAT-) to the active state (NFAT+). It is this transition that triggers the process of further profound lymphocyte activation.

Pharmacological targets and drugs

A detailed understanding of the mechanisms of intercellular interaction and intracellular signal transduction has made it possible to develop drugs capable of controlling the immune response. In pharmacology, two key points of application are distinguished to block T-lymphocyte activation at early stages.

The first target is the CD3 receptor, which is responsible for initiating the very first signal. The drug muromonab-CD3 specifically binds to this receptor on the T-lymphocyte surface. By blocking the receptor, the drug prevents antigen recognition and makes contact with the MHC complex of the antigen-presenting cell impossible.

The second target is inside the cell — the calcineurin enzyme. Such well-known drugs as ciclosporin and tacrolimus penetrate the cytoplasm and targetedly inhibit calcineurin (CaN). As a result of their action, the activation of the nuclear factor NFAT is blocked. The signaling cascade is interrupted at the very early stage, and the T lymphocyte remains inactive even if primary contact with the antigen-presenting cell has already taken place.

Class and exam questions

What else to study on this topic

• Further stages of active NFAT factor functioning in the cell nucleus
• Role and functions of antigen-presenting cells (APCs) in the immune response
• Differences in the activation mechanisms of T lymphocytes and B lymphocytes
• Mechanisms of action of other groups of immunosuppressants

Other topics in the section "Antigout drugs"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.