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The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in inflammatory disease models. The differential ability of Tc17 differentiation was not related to T-cell receptor (TCR) diversity and antigen specificity but was inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon was linked to differential levels of intrinsic TCR sensitivity and basal SMAD3 expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.

The strength of the T cell receptor interaction with self-ligands affects antigen-specific immune responses. However, the precise function and underlying mechanisms are unclear. Here, we demonstrate that naive CD8+T cells with relatively high self-reactivity are phenotypically heterogeneous owing to varied responses to type I interferon, resulting in three distinct subsets, CD5loLy6C–, CD5hiLy6C–, and CD5hiLy6C+cells. CD5hiLy6C+cells differ from CD5loLy6C–and CD5hiLy6C–cells in terms of gene expression profiles and functional properties. Moreover, CD5hiLy6C+cells demonstrate more extensive antigen-specific expansion upon viral infection, with enhanced differentiation into terminal effector cells and reduced memory cell generation. Such features of CD5hiLy6C+cells are imprinted in a steady-state and type I interferon dependence is observed even for monoclonal CD8+T cell populations. These findings demonstrate that self-reactivity controls the functional diversity of naive CD8+T cells by co-opting tonic type I interferon signaling.

STAT1 serves as a gatekeeper for naïve CD8 + T cell homeostasis by restraining type I IFN-STAT4-mTOR signaling axis.

BackgroundCD8+ tumor-infiltrating lymphocytes (TILs) comprise phenotypically and functionally heterogeneous subpopulations. Of these, effector memory CD45RA re-expressing CD8+ T cells (Temra) have been discovered and characterized as the most terminally differentiated subset. However, their exact ontogeny and physiological importance in association with tumor progression remain poorly understood.MethodsWe analyzed primary tumors and peripheral blood samples from 26 patients with non-small cell lung cancer and analyzed their phenotypes and functional characteristics using flow cytometry, RNA-sequencing, and bioinformatics.ResultsWe found that tumor-infiltrating Temra (tilTemra) cells largely differ from peripheral blood Temra (pTemra), with distinct transcriptomes and functional properties. Notably, although majority of the pTemra was CD27−CD28− double-negative (DN), a large fraction of tilTemra population was CD27+CD28+ double-positive (DP), a characteristic of early-stage, less differentiated effector cells. Trajectory analysis revealed that CD8+ TILs undergo a divergent sequence of events for differentiation into either DP or DN tilTemra. Such a differentiation toward DP tilTemra relied on persistent expression of CD27 and CD28 and was associated with weak T cell receptor engagement. Thus, a higher proportion of DP Temra was correlated with lower immunogenicity of tumor antigens and consequently lower accumulation of CD8+ TILs.ConclusionsThese data suggest a complex interplay between CD8+ T cells and tumors and define DP Temra as a unique subset of tumor-specific CD8+ TILs that are produced in patients with relatively low immunogenic cancer types, predicting immunogenicity of tumor antigens and CD8+ TIL counts, a reliable biomarker for successful cancer immunotherapy.

Background Silibinin is a flavonoid with antihepatotoxic properties, and exhibits pleiotropic anticancer effects. However, the molecular mechanisms responsible for its anticancer actions in pancreatic cancer cells, and the effects on such cells and normal pancreatic cells, remain unclear. The objective of this study was to determine the effect of silibinin on human pancreatic cancer cells and normal ductal cells.Methods Human pancreatic cancer cells (MIA PaCa-2 and PANC-1) and normal ductal cells (hTERT-HPNE) were cultured with 0–400 μM silibinin for 48 h. Thereafter, the proliferation, invasion, apoptosis, and signaling pathways of the pancreatic cells were evaluated.Results Silibinin significantly inhibited the proliferation, invasion, and spheroid formation of human pancreatic cancer cells in vitro in a dose-dependent manner (p < 0.05). It also induced apoptosis in a dose-dependent manner. Western blot analysis showed that silibinin downregulated extracellular signaling-regulated kinase (ERK) and serine/threonine protein kinase (AKT) in human pancreatic cancer cells. It also upregulated microtubule associated protein 1 light chain 3 β (LC3B) and cleaved caspase-3 via c-Jun N-terminal kinases (JNK) signaling. On the other hand, silibinin increased the mRNA and protein levels of c-Jun, Twist-related protein 1, and Snail. It also decreased exogenous p53 levels, but increased endogenous c-Jun protein levels in human pancreatic cancer cells. However, silibinin did not affect cell viability and endogenous c-Jun levels in pancreatic normal ductal cells. It increased exogenous p53 levels, but decreased stemness-related gene expression in pancreatic normal ductal cells. Silibinin increased Ki-67 levels in pancreatic cancer cells, but decreased them in pancreatic normal ductal cells.Conclusion Silibinin not only exerted anticancer effects by inhibiting AKT–ERK and JNK signaling, but also upregulated cancer stemness–related genes in human pancreatic cancer cells. These results suggest that silibinin should be used as a therapeutic agent for human pancreatic cancer with caution.

Capicua (CIC) is a transcriptional repressor that regulates several developmental processes. CIC deficiency results in lymphoproliferative autoimmunity accompanied by expansion of CD44hiCD62Llo effector/memory and follicular Th cell populations. Deletion of Cic alleles in hematopoietic stem cells (Vav1-Cre-mediated knockout of Cic) causes more severe autoimmunity than that caused by the knockout of Cic in CD4+CD8+ double positive thymocytes (Cd4-Cre-mediated knockout of Cic). In this study, we compared splenic CD4+ T cell activation and proliferation between whole immune cell-specific Cic-null (Cicf/f;Vav1-Cre) and T cell-specific Cic-null (Cicf/f;Cd4-Cre) mice. Hyperactivation and hyperproliferation of CD4+ T cells were more apparent in Cicf/f;Vav1-Cre mice than in Cicf/f;Cd4-Cre mice. Cicf/f;Vav1-Cre CD4+ T cells more rapidly proliferated and secreted larger amounts of IL-2 upon TCR stimulation than did Cicf/f;Cd4-Cre CD4+ T cells, while the TCR stimulation-induced activation of the TCR signaling cascade and calcium flux were comparable between them. Mixed wild-type and Cicf/f;Vav1-Cre bone marrow chimeras also exhibited more apparent hyperactivation and hyperproliferation of Cic-deficient CD4+ T cells than did mixed wild-type and Cicf/f;Cd4-Cre bone marrow chimeras. Taken together, our data demonstrate that CIC deficiency at the beginning of T cell development endows peripheral CD4+ T cells with enhanced T cell activation and proliferative capability.

Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naive T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8+T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8+ T cells than naive cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8+ T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens. Naive T cells establish self-tolerance via negative selection of cells with strong reactivity for self-peptide/MHC complexes, but undergo T-cell receptor (TCR) desensitisation when leaving the thymus. Here, Choet al.show that TCR desensitisation correlates with cell-surface density of the phosphatase CD45.

Objective Recent studies have revealed a link between Toll-like receptor (TLR) signaling and the adipose tissue inflammation associated with obesity. Although TLR9 is known to play an important role in inflammation and innate immunity, its role in mediating adipose tissue inflammation has not yet been investigated. Thus, the objective of this study was to determine the role of TLR9 in regulating immune cells in visceral adipose tissue and maintaining the metabolic homeostasis. Methods Wild-type and TLR9-deficient mice were fed with a high-fat diet, and the body weight gain, glucose tolerance, insulin sensitivity, and adipose tissue inflammation were examined. Results TLR9-deficient mice gained significantly more weight and body fat under a high-fat diet than wild-type mice and exhibited more severe glucose intolerance and insulin resistance. We also found a dramatic increase of M1 macrophages as well as TH1 cells in the adipose tissue of TLR9-deficient mice compared to wild-type mice. Furthermore, the levels of various proinflammatory cytokines and chemokines were higher in TLR9-deficient mice. Conclusions TLR9 signaling is involved in regulating adipose tissue inflammation and controlling obesity and the metabolic syndrome.

Background & Aims Obesity and metabolic syndrome have been associated with alterations to the intestinal microbiota. However, few studies examined the effects of obesity on the intestinal immune system. We investigated changes in subsets of intestinal CD4 + T-helper (T H ) cells with obesity and the effects of gut-tropic T H 17 cells in mice on a high-fat diet (HFD). Methods We isolated immune cells from small intestine and adipose tissue of C57BL/6 mice fed a normal chow diet or a HFD for 10 weeks and analyzed the cells by flow cytometry. Mice fed a vitamin A−deficient HFD were compared with mice fed a vitamin A−sufficient HFD. Obese RAG1-deficient mice were given injections of only regulatory T cells or a combination of regulatory T cells and T H 17 cells (wild type or deficient in integrin β7 subunit or interleukin 17 [IL17]). Mice were examined for weight gain, fat mass, fatty liver, glucose tolerance, and insulin resistance. Fecal samples were collected before and after T cell transfer and analyzed for microbiota composition by metagenomic DNA sequencing and quantitative polymerase chain reaction. Results Mice placed on a HFD became obese, which affected the distribution of small intestinal CD4 + T H cells. Intestinal tissues from obese mice had significant reductions in the proportion of T H 17 cells but increased proportion of T H 1 cells, compared with intestinal tissues from nonobese mice. Depletion of vitamin A in obese mice further reduced the proportion of T H 17 cells in small intestine; this reduction correlated with more weight gain and worsening of glucose intolerance and insulin resistance. Adoptive transfer of in vitro−differentiated gut-tropic T H 17 cells to obese mice reduced these metabolic defects, which required the integrin β7 subunit and IL17. Delivery of T H 17 cells to intestines of mice led to expansion of commensal microbes associated with leanness. Conclusions In mice, intestinal T H 17 cells contribute to development of a microbiota that maintains metabolic homeostasis, via IL17. Gut-homing T H 17 cells might be used to reduce metabolic disorders in obese individuals.

In this study investigated what buyers want and expect from medical equipment industry. In this study we found as fellows, (a) The quality of instrument is the most important factors that lead to customer purchase intent and brand image follwed by reliability and efficiency in order; (b) Customers perception of company did not show any meaningful relationship with brand image suggesting company positive image perceived by the customers would not necessarily have a positive impact on brand image. Rather, if brand image customer perceived gets higher, considerably higher purchase intention was observed. Therefore, the findings from the present study suggest that medical instrument manufactures need to focus more on providing a long-term high quality of service marketing strategy to increase customer satisfaction and purchase intent in this competitive business environment.

Recent studies have revealed a link between Toll-like receptor (TLR) signaling and the adipose tissue inflammation associated with obesity. Although TLR9 is known to play an important role in inflammation and innate immunity, its role in mediating adipose tissue inflammation has not yet been investigated. Thus, the objective of this study was to determine the role of TLR9 in regulating immune cells in visceral adipose tissue and maintaining the metabolic homeostasis.Wild-type and TLR9-deficient mice were fed with a high-fat diet, and the body weight gain, glucose tolerance, insulin sensitivity, and adipose tissue inflammation were examined.TLR9-deficient mice gained significantly more weight and body fat under a high-fat diet than wild-type mice and exhibited more severe glucose intolerance and insulin resistance. We also found a dramatic increase of M1 macrophages as well as TH 1 cells in the adipose tissue of TLR9-deficient mice compared to wild-type mice. Furthermore, the levels of various proinflammatory cytokines and chemokines were higher in TLR9-deficient mice.TLR9 signaling is involved in regulating adipose tissue inflammation and controlling obesity and the metabolic syndrome.

A gastric carcinoma with the endoscopic features resembling a submucosal tumor (SMT) is rare, and reportedly accounting for 0.1% to 0.63% of all resected gastric carcinomas in Japan. A diagnosis of a SMT-like gastric carcinoma is often difficult as the tumors are almost entirely covered with normal mucosa. Furthermore mucinous gastric adenocarcinoma is uncommon histologic subtype of gastric cancer. These tumors are detected mostly in an advanced stage and rarely in an early stage. Early mucinous gastric adenocarcinoma is characterized as an elevated lesion resembling SMT due to abundant mucin pools in the submucosa. Here we report one case of SMT-like mucinous gastric adenocarcinoma, diagnosed by the usual endoscopic biopsy and treated with surgery.

Pseudohypoparathyroidism is a rare disease that is characterized by target cell resistance to the effects of parathyroid hormone and this disease is classified into various types depending on the phenotypic and biochemical findings. The patients with pseudohypo parathyroidism present with the clinical and biochemical features of hypoparathyroidism, but they have an increased serum level of parathyroid hormone. We experienced a case of pseudohypoparathyroidism in a 24 years old woman who had Graves’ disease at that time. She had hypocalcemia, hyperphosphatemia, an elevated serum parathyroid hormone level and a normal urinary basal cyclic AMP(adenosine monophosphate) level. She also had a normal phenotypic appearance. Therefore, she was classified as suf fering with pseudohypoparathyroidism type II. The clinical and laboratory abnormalities were improved by calcium supplementa tion in addition to vitamin D. To the best of our knowledge, this is the first case of pseudohypoparathyroidism combined with Graves’ disease in Korea. (Endocrinol Metab 25:221-225, 2010)