Masakatsu Yamashita

Appropriate regulation of the differentiation balance between effector CD8 ⁺ T cells and memory CD8 ⁺ T cells is crucial for an appropriate immune response. We previously reported that the tumor suppressor menin suppresses the differentiation of CD8 ⁺ T cells into short‐lived effector T cells (SLECs) and positively regulates memory CD8 ⁺ T cell differentiation. In this study, we identified Ezh2, a histone H3K27 methyltransferase, as a factor responsible for regulating SLECs differentiation, located downstream of menin. In antigen‐stimulated CD8 ⁺ T cells, the Ezh2 expression gradually decreased with proliferation, reaching the lowest levels in terminally differentiated CD8 ⁺ T cells. The decrease in the expression of Ezh2 was accelerated by menin deficiency. Reduced histone H3K27 acetylation at the Ezh2 locus was observed in Menin ‐deficient CD8 ⁺ T cells, indicating that menin is required for maintaining the expression of Ezh2. In vitro studies have demonstrated that Ezh2 ‐deficient activated CD8 ⁺ T cells exhibit enhanced differentiation into SLECs, along with increased effector functions. In contrast, Ezh2‐deficient effector CD8 ⁺ T cells showed a marked increase in apoptosis upon IL‐2 removal. In studies using mouse tumor models, T cell‐specific Ezh2 knockout mice exhibited increased tumor growth and reduced survival relative to wild‐type mice, with a significant decrease in the number of tumor‐infiltrating CD8 ⁺ T cells. RNA sequencing revealed that Ezh2 ‐deficient effector CD8 ⁺ T cells exhibit the increased expression of terminal differentiation‐related molecules and apoptosis‐related genes. These results demonstrate that Ezh2 functions downstream of menin and is essential for the proper regulation of T cell‐dependent antitumor immunity.

General anesthesia is thought to suppress the immune system and negatively affect postoperative infection and the long-term prognosis of cancer. However, the mechanism underlying immunosuppression induced by general anesthetics remains unclear. In this study, we focused on propofol, which is widely used for sedation under general anesthesia and intensive care and examined its effects on the T cell function and T cell-dependent immune responses. We found that propofol suppressed T cell glycolytic metabolism, differentiation into effector T cells, and cytokine production by effector T cells. CD8 T cells activated and differentiated into effector cells in the presence of propofol in vitro showed reduced antitumor activity. Furthermore, propofol treatment suppressed the increase in the number of antigen-specific CD8 T cells during Listeria infection. In contrast, the administration of propofol improved inflammatory conditions in mouse models of inflammatory diseases, such as OVA-induced allergic airway inflammation, hapten-induced contact dermatitis, and experimental allergic encephalomyelitis. These results suggest that propofol may reduce tumor and infectious immunity by suppressing the T cell function and T cell-dependent immune responses while improving the pathogenesis and prognosis of chronic inflammatory diseases by suppressing inflammation.

Background: Abnormal immunity in the periphery has been reported in the pathogenesis of Alzheimer's disease (AD). Objective: In this study, blood transcriptome analyses of patients with AD, those with mild cognitive impairment (MCI) due to AD, and heathy controls were performed to elucidate immune-related pathophysiology. Methods: The sample included 63 participants from a complete enumeration study of elderly people in Nakayama town (the Nakayama Study), who were over 65 years of age, diagnosed as (1) healthy controls (N = 21, mean age: 83.8 years), (2) having MCI due to AD (N = 20, mean age: 82.6 years), or (3) having AD (N = 21, mean age: 84.2 years). Every participant underwent blood tests, magnetic resonance imaging, and questionnaires about lifestyle and cognitive function. With transcriptome analysis, differential gene expressions in the blood of the three groups were evaluated by gene ontology, pathway enrichment, and ingenuity pathway analyses, and quantitative real-time PCR was performed. Results: Neutrophil extracellular trap signaling was increased, and lipid metabolism (FXR/RXR activation, triacylglycerol degradation) was decreased in AD, whereas MCI showed protective responses via decreased neutrophil extracellular trap signaling and mitochondrial functions such as upregulation of the sirtuin pathway and downregulation of oxidative stress. Conclusions: Based on these findings and consistent with other published studies, immune cells appear to have important roles in the pathogenesis of AD, and the transcriptome in blood may be useful as a biomarker for diagnosis via monitoring immunity in MCI and AD.

Recent evidence suggests an association between age-related osteoporosis and cellular senescence in the bone; however, the specific bone cells that play a critical role in age-related osteoporosis and the mechanism remain unknown. Results revealed that age-related osteoporosis is characterized by the loss of osteoblast Men1. Osteoblast-specific inducible knockout of Men1 caused structural changes in the mice bones, matching the phenotypes in patients with age-related osteoporosis. Histomorphometrically, Men1-knockout mice femurs decreased osteoblastic activity and increased osteoclastic activity, hallmarks of age-related osteoporosis. Loss of Men1 induces cellular senescence via activation of mTORC1 pathway, rescued by metformin treatment. In bone morphogenetic protein-indued bone model, loss of Men1 leads to accumulation of senescent cells and osteoporotic bone formation, which are ameliorated by metformin. Our results indicate that cellular senescence in osteoblasts plays a critical role in age-related osteoporosis and that osteoblast-specific inducible Men1-knockout mice offer a promising model for developing therapeutics for age-related osteoporosis.

It has been suggested that aging of the immune system (immunosenescence) results in a decline in the acquired immune response, which is associated with an increase in age‐related tumorigenesis. T‐cell senescence plays a critical role in immunosenescence and is involved in the age‐related decline of the immune function, which increases susceptibility to certain cancers. However, it has been shown that CD8⁺ T cells with the senescent T‐cell phenotype acquire an natural killer (NK) cell‐like function and are involved in tumor elimination. Therefore, the role of senescent CD8⁺ T cells in tumor immunity remains to be elucidated. In this study, we investigated the role of senescent CD8⁺ T cells in tumor immunity. In a murine model of transferred with B16 melanoma, lung metastasis was significantly suppressed in aged mice (age ≥30 weeks) in comparison to young mice (age 6–10 weeks). We evaluated the cytotoxic activity of CD8⁺ T cells in vitro and found that CD8⁺ T cells from aged mice activated in vitro exhibited increased cytotoxic activity in comparison to those from young mice. We used Menin‐deficient effector T cells as a model for senescent CD8⁺ T cells and found that cytotoxic activity and the expression of NK receptors were upregulated in Menin‐deficient senescent CD8⁺ T cells. Furthermore, Menin‐deficient CD8⁺ T cells can eliminate tumor cells in an antigen‐independent manner. These results suggest that senescent effector CD8⁺ T cells may contribute to tumor immunity in the elderly by acquiring NK‐like innate immune functions, such as antigen‐independent cytotoxic activity.

CD8⁺ T cells play a central role in antitumor immune responses. Epigenetic gene regulation is essential to acquire the effector function of CD8⁺ T cells. However, the role of Utx, a demethylase of histone H3K27, in antitumor immunity remains unclear. In this study, we examined the roles of Utx in effector CD8⁺ T‐cell differentiation and the antitumor immune response. In a murine tumor‐bearing model, an increased tumor size and decreased survival rate were observed in T‐cell‐specific Utx KO (Utx KO) mice compared with wild‐type (WT) mice. The number of CD8⁺ T cells in tumor‐infiltrating lymphocytes (TILs) was significantly decreased in Utx KO mice. We found that the acquisition of effector function was delayed and attenuated in Utx KO CD8⁺ T cells. RNA sequencing revealed that the expression of effector signature genes was decreased in Utx KO effector CD8⁺ T cells, while the expression of naïve or memory signature genes was increased. Furthermore, the expression of Cxcr3, which is required for the migration of effector CD8⁺ T cells to tumor sites, was substantially decreased in Utx KO CD8⁺ T cells. These findings suggest that Utx promotes CD8⁺ T‐cell‐dependent antitumor immune responses partially through epigenetic regulation of the effector function.