How our immune system's natural killers are fine-tuned to fight cancer

Immunology Updates: The Role of NK Cells in Immune Defense
Natural Killer (NK) cells, an essential part of our body's immune system, are a unique type of lymphocyte responsible for detecting and eliminating cells that pose a threat, such as those infected by viruses or transformed into cancer cells. Unlike other immune cells, NK cells do not require prior sensitization to recognize and destroy harmful cells, making them a crucial component of the innate immune response. Their ability to kill target cells on the spot is particularly valuable in combating tumors and viral infections. However, this cytotoxic power must be carefully regulated to prevent unintended damage to healthy tissues, and this regulation is an ongoing area of research. This Immunology Updates news report explores the intricate mechanisms that control NK cell activity, drawing on recent findings from researchers at the Faculty of Medicine, University of Rijeka in Croatia, who are shedding light on how NK cells maintain this delicate balance.


 How our immune system's natural killers are fine-tuned to fight cancer

Understanding NK Cell Activation
NK cells operate based on a balance system that integrates signals from both activating and inhibitory receptors on their surface. For NK cells to spring into action, the cumulative effect of activating signals must outweigh the inhibitory ones. This system ensures that NK cells only target cells that display abnormal characteristics, such as the absence of MHC-I molecules or the presence of stress-induced ligands. MHC-I molecules, commonly found on healthy cells, provide inhibitory signals that prevent NK cell activation. When these molecules are missing or reduced, as often occurs during viral infections or in cancer cells, the inhibitory signals decrease, tipping the balance towards activation - a process known as "missing self" recognition.
 
The Complexity of NK Cell Receptors
NK cells express a wide array of receptors, which can be broadly categorized into activating and inhibitory types. Activating receptors, such as NKG2D, NKp46, and DNAM-1, recognize abnormal ligands on potential target cells, triggering the NK cell to attack. For example, the NKG2D receptor plays a vital role in detecting and eliminating virus-infected and tumor cells. In contrast, inhibitory receptors, including those in the Ly49 family in mice and KIR family in humans, recognize self-MHC-I molecules, ensuring that NK cells do not mistakenly destroy healthy cells.
 
One of the fascinating aspects of NK cell biology is the presence of paired receptors - activating and inhibitory receptors that recognize the same ligands. This pairing adds another layer of regulation, fine-tuning NK cell responsiveness and preventing unnecessary activation. For instance, in mice, the Ly49I inhibitory receptor recognizes the same MCMV-encoded protein as the Ly49H activating receptor, a mechanism that evolved to counteract viral evasion strategies.
 
Regulating NK Cell Responsiveness
NK cell activity is not static; it is fine-tuned during development and in the peri phery, where these cells encounter potential threats. During development, NK cells undergo a process known as education or licensing, where they learn to distinguish between healthy and abnormal cells. This education involves interactions with self-MHC-I molecules through inhibitory receptors, ensuring that NK cells become functional yet self-tolerant. Interestingly, this licensing process is not set in stone. NK cells can adjust their responsiveness based on environmental changes, a phenomenon demonstrated by the restoration of NK cell function in MHC-I-deficient mice when these cells were transferred to an MHC-I-sufficient environment.
 
In addition to education, NK cells can modify their receptor repertoire in response to the loss of certain receptors, ensuring that they maintain an optimal activation threshold. For example, in mice lacking the NKG2D receptor, NK cells compensate by upregulating other activating receptors like DNAM-1. This adaptability highlights the remarkable plasticity of NK cells and their ability to maintain effective immune surveillance even when some receptors are missing.
 
Memory NK Cells: An Enhanced Line of Defense
Recent research has revealed that NK cells, much like T cells, can develop memory-like properties, allowing them to mount a more robust response upon re-exposure to a pathogen. This discovery challenges the traditional view of NK cells as purely innate immune cells with no memory capability. Memory NK cells have been observed in response to certain viral infections, such as murine cytomegalovirus (MCMV), and can persist for extended periods, providing long-term protection.
 
Memory NK cells exhibit distinct changes in their receptor expression and activation thresholds, making them more responsive to subsequent challenges. For example, in the context of MCMV infection, memory NK cells display higher levels of the Ly49H receptor and produce more cytokines like IFNγ, enhancing their ability to control the infection.
 
Implications for Cancer Immunotherapy
The unique properties of NK cells make them attractive candidates for cancer immunotherapy. Unlike T cells, NK cells do not require antigen presentation via HLA molecules, allowing them to target a broader range of tumor cells. Moreover, NK cells can be engineered to express Chimeric Antigen Receptors (CARs), similar to CAR T cells, enabling them to recognize and attack specific tumor antigens.

However, NK cell-based therapies face challenges, such as ensuring that the engineered cells retain their functionality and do not induce adverse effects like cytokine release syndrome. Researchers are also exploring NK cell engagers (NKCEs), synthetic molecules that simultaneously bind activating receptors on NK cells and tumor antigens, offering a promising alternative to CAR NK cell therapy.
 
Conclusions
Natural Killer cells represent a powerful component of the immune system with significant potential for therapeutic applications, particularly in cancer immunotherapy. The intricate balance of activating and inhibitory signals that govern NK cell activity is crucial for their effective function. Recent research has illuminated the remarkable adaptability of NK cells, from their ability to fine-tune receptor expression to the development of memory-like properties that enhance their responsiveness. As we continue to unravel the complexities of NK cell biology, these insights will pave the way for more effective and targeted immunotherapies, harnessing the full potential of these natural-born killers to fight cancer and other diseases.
 
The study findings were published in the peer-reviewed journal: Cells.
https://www.mdpi.com/2073-4409/13/17/1464
 
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https://www.thailandmedical.news/news/natural-killer-cell-receptor-modulation-in-viral-infections-current-insights