regulation of leukocyte mediated cytotoxicity

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate, or extent of leukocyte mediated cytotoxicity. [GOC:add, ISBN:0781735149, PMID:11911826]

Leukocyte-mediated cytotoxicity is a complex process involving the coordinated action of various immune cells to eliminate target cells, such as infected cells or tumor cells. This process is tightly regulated to ensure that only appropriate targets are destroyed, while healthy cells are spared. Here's a detailed breakdown of the biological process:

**1. Recognition of Target Cells:**

* **Antigen Presentation:** Immune cells like macrophages and dendritic cells engulf and process antigens from pathogens or tumor cells. They then present these antigens on their surface using MHC (major histocompatibility complex) molecules.
* **T Cell Activation:** CD8+ T lymphocytes (cytotoxic T lymphocytes or CTLs) recognize antigen-MHC complexes on target cells through their T cell receptors (TCRs). This interaction, along with signals from co-stimulatory molecules, activates the T cell.

**2. Signal Transduction and Polarization:**

* **Activation of Signaling Pathways:** TCR engagement triggers a cascade of intracellular signaling pathways, leading to the production of transcription factors that regulate gene expression in the T cell.
* **Polarization:** Activated T cells undergo cytoskeletal reorganization, forming an immunological synapse with the target cell. This involves the localization of cytotoxic molecules (e.g., perforin and granzyme) towards the contact site.

**3. Cytotoxic Molecule Delivery:**

* **Exocytosis:** T cells release cytotoxic molecules, including perforin and granzymes, from specialized secretory granules. These molecules are directed towards the target cell through the immunological synapse.
* **Perforin:** Perforin forms pores in the target cell membrane, disrupting its integrity and allowing the entry of granzymes.
* **Granzymes:** Granzymes are proteases that enter the target cell through the perforin-created pores. They activate apoptotic pathways, leading to programmed cell death.

**4. Cell Death and Clearance:**

* **Apoptosis:** Granzyme-induced caspase activation triggers a cascade of events that dismantle the target cell's internal structures, leading to its fragmentation.
* **Phagocytosis:** Phagocytic cells, such as macrophages, engulf and digest the apoptotic fragments, removing them from the body.

**5. Regulatory Mechanisms:**

* **Immune Checkpoint Molecules:** To prevent excessive cytotoxicity and autoimmunity, inhibitory receptors (e.g., CTLA-4, PD-1) are expressed on activated T cells. These molecules interact with ligands on antigen-presenting cells or target cells, downregulating T cell activation and preventing excessive killing.
* **Cytokine Regulation:** Cytokines, such as IL-2 and IFN-gamma, play a role in fine-tuning the immune response by regulating the activation, differentiation, and survival of various immune cells.

**6. Role of Natural Killer (NK) Cells:**

* **NK Cell Recognition:** Natural killer (NK) cells are innate immune cells that can kill target cells without prior sensitization to specific antigens. They recognize and eliminate target cells that lack MHC expression or display stress signals, such as tumor cells or virally infected cells.
* **NK Cell Mechanisms:** NK cells utilize cytotoxic mechanisms similar to CTLs, including the release of perforin and granzymes.

**7. Dysregulation and Implications:**

* **Autoimmune Diseases:** Dysregulation of leukocyte-mediated cytotoxicity can lead to autoimmune diseases, where the immune system attacks healthy tissues.
* **Cancer:** Defects in immune surveillance mechanisms, including leukocyte-mediated cytotoxicity, can contribute to cancer development and progression.
* **Infections:** Impaired leukocyte-mediated cytotoxicity can increase susceptibility to infections and hinder the ability to control pathogen spread.

This intricate process ensures the effective elimination of harmful cells while minimizing collateral damage to healthy tissues. The balance between activation and inhibition of leukocyte-mediated cytotoxicity is crucial for maintaining immune homeostasis.'
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Compounds (13)