Lymphokine-activated killers

Origin and activation of LAK cells

Lymphokine-activated killer cells are formed predominantly from the pool of natural killer (NK) cells under the influence of specific humoral factors. The most powerful stimulator of this process is interleukin-2 (IL-2). There are other cytokines capable of triggering a similar transformation, but their efficacy is significantly lower. These include:

• Interleukin-7 (IL-7)
• Interleukin-1 (IL-1)
• Granulocyte-macrophage colony-stimulating factor (GM-CSF)
• Interleukin-4 (IL-4)
• Various interferons

It is important to note that to date, the formation of LAK cells under natural conditions in the human body (in vivo) has no scientific proof. In clinical practice, they are obtained exclusively by artificial means (in vitro). For this purpose, mononuclear cells isolated from the blood of cancer patients are cultured in the presence of IL-2. The resulting active cell mass is then used in the combination therapy of malignant tumors.

Molecular mechanisms and features of cytolysis

The process of transforming a normal NK cell into a hyperactive LAK cell is not yet fully understood. Nevertheless, a key marker of this transition has been reliably established: the appearance of a specific activation receptor NKp44 on the membrane surface, which belongs to the natural cytotoxicity receptor (NCR) group. It is believed that the expression of NKp44 provides a sharp increase in killer activity and significantly expands the spectrum of potential target cells.

Under normal conditions, killer activity is strictly controlled: lysis of syngeneic (autologous) cells of the body is prohibited if major histocompatibility complex class I (MHC-I) is present on their surface. In LAK cells, this restriction is formally preserved. However, due to a powerful shift in the balance of stimulating signals toward the activation of lysis, the role of this inhibitory mechanism is significantly reduced, allowing LAK cells to attack even those targets that normal NK cells would ignore.

Evolutionary role and target selection

The main biological task of natural killer cells is the elimination of cells that have lost MHC-I molecules (the "self" marker) and simultaneously acquired stress molecules (danger markers) on their surface. Such a picture is most typical for tumor transformation or viral infection, as these processes are often accompanied by the suppression of MHC-I expression.

From an evolutionary standpoint, the decrease in the amount of MHC-I on the membrane is a defense mechanism of the altered cell, its attempt to "escape" recognition by antigen-specific cytotoxic T lymphocytes (T killers). Since T killers cannot attack a cell without MHC-I, the immune system required a reserve mechanism. Based on this, biologists suggest that NK cells emerged somewhat later than T lymphocytes in the course of evolution, acting as a compensatory tool for destroying such "invisible" threats.

Cytotoxicity balance: NK cells vs. T lymphocytes

The fate of any potentially dangerous cell strictly depends on the balance of two factors on its surface: the level of MHC-I molecule expression and the presence of stress molecules. The immune system distributes roles as follows:

1. The cell maintains normal MHC-I expression. In this case, it is an ideal target for cytotoxic T lymphocytes if it presents a foreign antigen. Natural killer cells will not attack such a cell due to inhibitory signals.
2. The cell loses MHC-I (or expresses it poorly) but carries stress molecules. T lymphocytes become blind to such a threat. However, the cell turns into a priority target for natural killer cells (and consequently, LAK cells).

Role of cytokines in the innate immunity system

Since the activation of LAK cells directly depends on interleukins, it is important to understand the place of these substances in the overall humoral system of innate immunity. The humoral link consists of several interrelated blocks: the complement system, the cytokine network, bactericidal peptides, and systems associated with inflammation.

The operation of these systems is based on two fundamental principles:

• The cascade principle (using the complement system as an example). Factors are involved in the defense reaction strictly sequentially, one after another. At the same time, biological effects can manifest both at the final stages of activation and at intermediate stages.
• The network principle (using cytokines as an example). Various components (for example, different interleukins) function simultaneously. The basis of the cytokine network's operation is close functional interrelation, mutual influence of molecules on each other, and their significant capacity for interchangeability (which explains why, in addition to IL-2, LAK cells can be stimulated by other cytokines).

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of action of NK cell activation and inhibition receptors
• Structural features and functions of MHC-I molecules
• The cascade principle in the complement system
• Bactericidal peptides and inflammatory humoral systems
• Methods of in vitro mononuclear cell cultivation for immunotherapy

Other topics in the "Innate Immunity" section

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