Natural Killer Cells as Immune Effectors for Selection, Differentiation and Resistance of Healthy and Transformed Stem Cells

Recent advancements in our understanding of anti-tumor immune responses and cancer biology have revealed an elaborate interaction between immune effectors as well as transformed cells in the tumor microenvironment. Effectors of the immune system are known to modulate the maturation of tumor cells and to select for cancer with reduced immunogenicity. The same effector mechanisms are likely responsible for shaping the development of healthy stem cells for the ultimate goal of repair and regeneration of damaged tissues and the discontinuation of chronic inflammation. Natural Killer (NK) cells were first described based on their ability to mediate tumor cell lysis without prior sensitization, however much of their effector functions and dynamic interaction with cells in the microenvironment are still not completely understood. Many studies have demonstrated that NK cells may recognize and become activated by irradiated or stressed cells; yet, currently no studies have investigated the role of NK cells in selection and differentiation of stem cells and potential role of NK cells in the resolution of inflammation. The established paradigm suggests that NK cells are only capable of eliminating defective cells that arise in the body; but, data obtained in this study indicate that the functions of NK cells are not as limited as we once thought. This study provides evidences that tumor cells and virally infected cells are not the only targets of NK cell-mediated cytotoxicity. Immune cells and healthy stem cells are also susceptible to lysis. NK cells obtained from the peripheral blood or those that have infiltrated into tumors have been shown to be cytotoxicity inactivated or also known as "anergized". In this study, an array of mediators that cause anergy in NK cells have been identified and extensively studied. Initiation of the anergic state in NK cells was once thought as an end-point, a last stop before apoptosis; however, presented data will demonstrate that anergy is a physiological stage that NK cells undergo to help support differentiation of stem cells. Taken together, all of the results provide a novel role for NK cells as effector cells in selection, differentiation and resistance of both transformed and healthy stem cells

Natural Killer Cells as Immune Effectors for Selection, Differentiation and Resistance of Healthy and Transformed Stem Cells

Recent advancements in our understanding of anti-tumor immune responses and cancer biology have revealed an elaborate interaction between immune effectors as well as transformed cells in the tumor microenvironment. Effectors of the immune system are known to modulate the maturation of tumor cells and to select for cancer with reduced immunogenicity. The same effector mechanisms are likely responsible for shaping the development of healthy stem cells for the ultimate goal of repair and regeneration of damaged tissues and the discontinuation of chronic inflammation. Natural Killer (NK) cells were first described based on their ability to mediate tumor cell lysis without prior sensitization, however much of their effector functions and dynamic interaction with cells in the microenvironment are still not completely understood. Many studies have demonstrated that NK cells may recognize and become activated by irradiated or stressed cells; yet, currently no studies have investigated the role of NK cells in selection and differentiation of stem cells and potential role of NK cells in the resolution of inflammation. The established paradigm suggests that NK cells are only capable of eliminating defective cells that arise in the body; but, data obtained in this study indicate that the functions of NK cells are not as limited as we once thought. This study provides evidences that tumor cells and virally infected cells are not the only targets of NK cell-mediated cytotoxicity. Immune cells and healthy stem cells are also susceptible to lysis. NK cells obtained from the peripheral blood or those that have infiltrated into tumors have been shown to be cytotoxicity inactivated or also known as "anergized". In this study, an array of mediators that cause anergy in NK cells have been identified and extensively studied. Initiation of the anergic state in NK cells was once thought as an end-point, a last stop before apoptosis; however, presented data will demonstrate that anergy is a physiological stage that NK cells undergo to help support differentiation of stem cells. Taken together, all of the results provide a novel role for NK cells as effector cells in selection, differentiation and resistance of both transformed and healthy stem cells

Osteonecrosis of the Jaw Developed in Mice DISEASE VARIANTS REGULATED BY γδ T CELLS IN ORAL MUCOSAL BARRIER IMMUNITY*

Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier γδ T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 μg/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. γδ T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated γδ T cell null (Tcrd(-/-) ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd(-/-) ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd(-/-) ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of γδ T cells from human peripheral blood (h-γδ T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-γδ T cells exhibited rapid expansion and robust IFN-γ secretion. When h-γδ T cells were injected into ZOL-treated immunodeficient (Rag2(-/-) ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2(-/-) ZOL mice did not develop osteonecrosis. The results indicate that γδ T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ

Osteonecrosis of the Jaw Developed in Mice

Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier γδ T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 μg/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. γδ T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated γδ T cell null (Tcrd(−/−) ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd(−/−) ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd(−/−) ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of γδ T cells from human peripheral blood (h-γδ T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-γδ T cells exhibited rapid expansion and robust IFN-γ secretion. When h-γδ T cells were injected into ZOL-treated immunodeficient (Rag2(−/−) ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2(−/−) ZOL mice did not develop osteonecrosis. The results indicate that γδ T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ