Initiation and Antigen Processing
The initiation of a specific immune response is invariably preceded by cell death and non-specific inflammation (at the site of infection, tumor necrosis, or tissue transplantation). Vascular endothelium responds to breakdown products by allowing granulocytes and monocytes to enter the tissues, where monocytes differentiate into macrophages.
Macrophages and other antigen-presenting cells (APCs) phagocytose foreign agents. Inside the APC, the antigen enters an endosome, where enzymes degrade it into short peptides (15–20 amino acids). Simultaneously, class II major histocompatibility complex (MHC class II) molecules are synthesized in the rough endoplasmic reticulum of the APC.
To prevent MHC class II from prematurely binding to the cell's own proteins during transport, its active site is blocked by an invariant chain (sometimes referred to as the "chastity belt"). The complex moves through the Golgi apparatus and fuses with the endosome. There, the protective chain is removed, and MHC class II binds peptides (both self and non-self) before being transported to the cell membrane. Statistically, only about 0.1% of these complexes carry the required foreign antigenic determinant.
Lymphoid Tissue Encounter and Activation
APCs bearing the processed antigen migrate from the inflammatory focus to the T-cell zones of peripheral lymphoid organs (such as the paracortical zone of lymph nodes). Here, lymphocyte clone selection takes place.
To ensure precise and coordinated help, a triple cell complex is formed: the APC simultaneously interacts with an inactive helper T cell and a cytotoxic T cell.
- Upon recognizing the antigen, the helper T cell releases interleukin-2, which stimulates its own division (autocrine regulation).
- Once matured, the helper T cell activates the neighboring cytotoxic T cell.
- The activated cytotoxic T cell transforms into an immunoblast and begins rapid division (clonal expansion), forming a pool of memory T cells and mature effector cells.
Importantly, only preparation occurs in the lymph nodes; the actual attack on target cells takes place in the periphery.
Effector Phase: Mechanisms of Destruction
Mature cytotoxic T cells leave the lymphoid tissue, locate target cells via antigenic determinants, and execute their cytotoxic function. There are two primary mechanisms of target cell destruction:
- Osmotic shock. The cytotoxic T cell releases the protein perforin. Perforin molecules insert themselves into the membrane of the target cell, forming hydrophilic pores. This disrupts the osmotic balance and leads to cell lysis.
- Apoptosis. Enzymes called granzymes enter the target cell through the perforin-formed pores. Additionally, the Fas receptor («death receptor») on the surface of the target cell is activated, triggering a cascade of programmed cell death.
Alternative Response Scenarios
Depending on the type of threat, the immune system may deviate from the classical interaction scheme:
- Viral infections: The response can bypass helper T cells. Cytotoxic T cells are activated directly by dendritic cells or independently recognize the altered target cell.
- Intracellular parasites (e.g., Rickettsia): Macrophages assume the primary effector role. Helper T cells merely provide them with a stimulating signal.
- Transplant rejection: Cytotoxic T cells are capable of attacking foreign tissues. This is hypothesized to occur due to somatic mutagenesis of T-cell receptor genes in dividing lymphocytes, resulting in the selection of clones with high affinity for foreign MHC class I molecules.