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A view to a kill: signals triggering cytotoxicity
Julie Y Djeu1, Kun Jiang, Sheng Wei
1Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, Florida 33612, USA. djeu@moffitt.usf.edu
Abstract:
Tumor immunity requires the participation of lymphocyte effector cells that display powerful processes to destroy malignant cells. Natural killer (NK) cells and CTLs, once activated, use the same lytic processes for mediating target cell death. However, they are triggered through distinctly separate antigen receptors. NK cells are currently known to express at least three families of receptors unrelated to the T cell receptor, i.e., NKG2, KIR, and NCR, to mediate cytotoxicity. This review provides a view to a kill, bringing together a unifying concept for a common signal pathway that dictates lytic function. What emerges is a specific Syk/Zap70 --> PI3K --> Rac --> PAK --> MEK --> ERK signal cascade triggered by target cell recognition, which is responsible for mobilizing the lytic granules containing perforin and granzyme B toward the contacted target cell.
Insights
Natural killer (NK) cells and CTLs use similar cell-killing processes but distinct receptors. A common signaling pathway involving Syk/Zap70, PI3K, and ERK activates NK cell cytotoxicity against tumor targets.
Area of Science:
- Immunology
- Cellular Biology
- Cancer Research
Background:
- Tumor immunity relies on effector lymphocytes like NK cells and CTLs to eliminate malignant cells.
- NK cells and CTLs employ similar cytotoxic mechanisms but are activated via separate antigen receptors.
- NK cells utilize NKG2, KIR, and NCR receptor families for cytotoxicity.
Purpose of the Study:
- To present a unifying concept for a common signaling pathway that regulates lytic function in NK cells.
- To elucidate the molecular cascade responsible for NK cell-mediated cytotoxicity.
Main Methods:
- Review of existing literature on NK cell receptors and signaling pathways.
- Analysis of signal transduction cascades involved in lymphocyte effector functions.
Main Results:
- A specific signaling cascade, Syk/Zap70 → PI3K → Rac → PAK → MEK → ERK, is identified as crucial for lytic function.
- This pathway is triggered upon target cell recognition by NK cells.
Conclusions:
- The identified signaling cascade provides a unified mechanism for NK cell-mediated cytotoxicity.
- Activation of this pathway mobilizes cytotoxic granules (containing perforin and granzyme B) towards target cells, facilitating tumor cell destruction.