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Chen, S., Zhu, H., & Jounaidi, Y. (2024). Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization. Signal Transduction and Targeted Therapy, 9(1), 302. Added by: Dr. Enrique Feoli (20/12/2025, 10:52) Last edited by: Dr. Enrique Feoli (20/12/2025, 12:31) |
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| Resource type: Journal Article DOI: 10.1038/s41392-024-02005-w ID no. (ISBN etc.): 2059-3635 BibTeX citation key: Chen2024 View all bibliographic details  |
Categories: BioAcyl Corp Subcategories: Microenvironment Keywords: Cancer microenvironment, Immunotherapy, Innate immunity Creators: Chen, Jounaidi, Zhu Collection: Signal Transduction and Targeted Therapy |
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| Abstract |
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Natural killer (NK) cells, initially identified for their rapid virus-infected and leukemia cell killing and tumor destruction, are pivotal in immunity. They exhibit multifaceted roles in cancer, viral infections, autoimmunity, pregnancy, wound healing, and more. Derived from a common lymphoid progenitor, they lack CD3, B-cell, or T-cell receptors but wield high cytotoxicity via perforin and granzymes. NK cells orchestrate immune responses, secreting inflammatory IFNγ or immunosuppressive TGFβ and IL-10. CD56dim and CD56bright NK cells execute cytotoxicity, while CD56bright cells also regulate immunity. However, beyond the CD56 dichotomy, detailed phenotypic diversity reveals many functional subsets that may not be optimal for cancer immunotherapy. In this review, we provide comprehensive and detailed snapshots of NK cells’ functions and states of activation and inhibitions in cancer, autoimmunity, angiogenesis, wound healing, pregnancy and fertility, aging, and senescence mediated by complex signaling and ligand-receptor interactions, including the impact of the environment. As the use of engineered NK cells for cancer immunotherapy accelerates, often in the footsteps of T-cell-derived engineering, we examine the interactions of NK cells with other immune effectors and relevant signaling and the limitations in the tumor microenvironment, intending to understand how to enhance their cytolytic activities specifically for cancer immunotherapy.
Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |
| Notes |
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Overall, the interactions of NK cells and T-cells with MHC I are quite similar but yield different outcomes. NK cell interrogation of MHC I creates a tolerance signal that accepts HLA polymorphisms unless HLA is completely missing, very polymorphic, or from another species. This tolerance signal is relevant to fetus implantation, transplantation, and rejection and is evident in the urochordate Botryllus. Schlosseri, the closest invertebrate to vertebrates, which has only NK cells with no T or B-cells.115,116,117 Each B. Schlosseri individual transplants daily with others to form chimeras, and each need only one common allele of Botryllus histocompatibility factor118,119,120 to transplant with another individual successfully. The B. Schlosseri histocompatibility complex allowing this transplantation has extensive polymorphism119 and the mechanism that controls the tolerance signal and success of transplantation is mediated by BsCD94-1gene, a CD94-related transmembrane receptor of vertebrate NK cells, expressed on the surface of a subpopulation of Botryllus blood cells and upregulated during the allorecognition process.121 CD94 is expressed in modern NK and CD8 T-cells to interact with non-classical MHC I HLA-E, presenting the leader sequence peptides of HLA-A, HLA-B, and HLA-C groups. CD94 associates as a heterodimer with NKG2C and DAP12 to activate NK and T-cells or with NKG2A to inhibit them. This suggests first that NK cells are more ancient than T-cells and second that original NK cells via MHC I may have been designed initially to identify the self but also to regulate asexual reproduction and tolerance between two close individuals.
Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |