The Effect of uranium-236 and neptunium-237 on the value of uranium used as feed for thermal power reactors

Statement of responsibility on title page reads: Manson Benedict, David J. Bauhs, Terence C. Golden and Edward A. Mason"June 30, 1968.""MIT-2073-7."Includes bibliographical references (pages 183-184)United States Atomic Energy Commission contract AT(30-1)-207

Distinct subpopulations of gy T cells are present in normal and tumor-bearing human liv

gy T cells are thought to mediate immune responses at epithelial surfaces. We have quantified and characterized hepatic and peripheral blood gy T cells from 11 normal and 13 unresolved tumor-bearing human liver specimens. gy T cells are enriched in normal liver (6.6% of T cells) relative to matched blood (0.9%; P = 0.008). The majority express CD4CD8 phenotypes and many express CD56 and/or CD161. In vitro, hepatic gy T cells can be induced to kill tumor cell lines and release interferon-g, tumor necrosis factor-a, interleukin-2 and interleukin- 4. Analysis of Vgand Vy chain usage indicated that Vy3+ cells are expanded in normal livers (21.2% of gy T cells) compared to blood (0.5%; P = 0.001). Tumor-bearing livers had significant expansions and depletions of gy T cell subsets but normal cytolytic activity. This study identifies novel populations of liver T cells that may play a role in immunity against tumors

Distinct subpopulations of gy T cells are present in normal and tumor-bearing human liv

gy T cells are thought to mediate immune responses at epithelial surfaces. We have quantified and characterized hepatic and peripheral blood gy T cells from 11 normal and 13 unresolved tumor-bearing human liver specimens. gy T cells are enriched in normal liver (6.6% of T cells) relative to matched blood (0.9%; P = 0.008). The majority express CD4CD8 phenotypes and many express CD56 and/or CD161. In vitro, hepatic gy T cells can be induced to kill tumor cell lines and release interferon-g, tumor necrosis factor-a, interleukin-2 and interleukin- 4. Analysis of Vgand Vy chain usage indicated that Vy3+ cells are expanded in normal livers (21.2% of gy T cells) compared to blood (0.5%; P = 0.001). Tumor-bearing livers had significant expansions and depletions of gy T cell subsets but normal cytolytic activity. This study identifies novel populations of liver T cells that may play a role in immunity against tumors

Interleukin 12 (IL-12) is increased in tumour bearing human liver and expands CD8C and CD56C T cells in vitro but not in vivo

Human liver is enriched with CD8CT- and CD3CCD56C natural T (NT)-lymphocytes, important anti-tumour effectors, similar to murine NKTs. IL-12 promotes anti-tumour functions of NKTs. We quantified IL-12 and CD56C/CD8CT lymphocytes in normal and tumour bearing liver. We also examined the effect of IL-12 on the expansion/activation of peripheral blood cells in vitro. IL-12 was detected in normal (n ¼ 13, median 2032 pg/100 mg protein) and increased in tumour bearing liver (n ¼ 9, 3678 pg, p!0:01). Infiltrating monocytes appear to be the principal producers. Culture with IL-12 selectively expanded CD8CT and CD3CCD56CNT cells and polarised their cytokine responses to Th1-type. However, there was no in vivo expansion of these cells in tumour bearing liver. Changes observed in culture required addition of IL-2. We therefore quantified IL-2 in hepatic tissue. IL-2 was detected in normal liver (median 4700 pg/100 mg protein). Surprisingly, there was no increase in tumour-infiltrated liver (4910 pg). The presence of IL-12 may create an environment in healthy liver that promotes the accumulation of CD8CT and CD56CNT cells. Therefore, the development of metastases in the presence of high levels of IL-12 may be due to an insufficient IL-12 response. Alternatively, lack of IL-2 rather than a defect in IL-12, may be responsible for insufficient expansion/activation of tumour specific cytotoxic T lymphocytes

Interleukin 12 (IL-12) is increased in tumour bearing human liver and expands CD8C and CD56C T cells in vitro but not in vivo

Human liver is enriched with CD8CT- and CD3CCD56C natural T (NT)-lymphocytes, important anti-tumour effectors, similar to murine NKTs. IL-12 promotes anti-tumour functions of NKTs. We quantified IL-12 and CD56C/CD8CT lymphocytes in normal and tumour bearing liver. We also examined the effect of IL-12 on the expansion/activation of peripheral blood cells in vitro. IL-12 was detected in normal (n ¼ 13, median 2032 pg/100 mg protein) and increased in tumour bearing liver (n ¼ 9, 3678 pg, p!0:01). Infiltrating monocytes appear to be the principal producers. Culture with IL-12 selectively expanded CD8CT and CD3CCD56CNT cells and polarised their cytokine responses to Th1-type. However, there was no in vivo expansion of these cells in tumour bearing liver. Changes observed in culture required addition of IL-2. We therefore quantified IL-2 in hepatic tissue. IL-2 was detected in normal liver (median 4700 pg/100 mg protein). Surprisingly, there was no increase in tumour-infiltrated liver (4910 pg). The presence of IL-12 may create an environment in healthy liver that promotes the accumulation of CD8CT and CD56CNT cells. Therefore, the development of metastases in the presence of high levels of IL-12 may be due to an insufficient IL-12 response. Alternatively, lack of IL-2 rather than a defect in IL-12, may be responsible for insufficient expansion/activation of tumour specific cytotoxic T lymphocytes

Innate Immune Function in Placenta and Cord Blood of Hepatitis C – Seropositive Mother-Infant Dyads

Vertical transmission accounts for the majority of pediatric cases of hepatitis C viral (HCV) infection. In contrast to the adult population who develop persistent viremia in ∼80% of cases following exposure, the rate of mother-to-child transmission (2–6%) is strikingly low. Protection from vertical transmission likely requires the coordination of multiple components of the immune system. Placenta and decidua provide a direct connection between mother and infant. We hypothesized that innate immune responses would differ across the three compartments (decidua, placenta and cord blood) and that hepatitis C exposure would modify innate immunity in these tissues. The study was comprised of HCV-infected and healthy control mother and infant pairs from whom cord blood, placenta and decidua were collected with isolation of mononuclear cells. Multiparameter flow cytometry was performed to assess the phenotype, intracellular cytokine production and cytotoxicity of the cells. In keeping with a model where the maternal-fetal interface provides antiviral protection, we found a gradient in proportional frequencies of NKT and γδ-T cells being higher in placenta than cord blood. Cytotoxicity of NK and NKT cells was enhanced in placenta and placental NKT cytotoxicity was further increased by HCV infection. HCV exposure had multiple effects on innate cells including a decrease in activation markers (CD69, TRAIL and NKp44) on NK cells and a decrease in plasmacytoid dendritic cells in both placenta and cord blood of exposed infants. In summary, the placenta represents an active innate immunological organ that provides antiviral protection against HCV transmission in the majority of cases; the increased incidence in preterm labor previously described in HCV-seropositive mothers may be related to enhanced cytotoxicity of NKT cells

Chronic HCV infection promotes cytotoxicity in antigen-specific CD8+ T cells regardless of virus specificity

IntroductionDespite advancements in hepatitis C virus (HCV) infection treatment, HCV still represents a significant public health burden. Besides progressive hepatic damage, viral persistence has lasting effects on innate and adaptive immune responses. Lack of a complete understanding of the factors driving an effective HCV response contributes to the failure to develop a vaccine for prevention. This study advances the existing knowledge on HCV-specific CD8+ T cells and describes the impact of current or past HCV infection on CD8+ T cells specific for other viruses.MethodsWe used barcoded-dextramers to identify and sort CD8+ T cells specific for HCV, cytomegalovirus, and influenza, and characterized them using single-cell RNA sequencing technology. Our cohort included chronic (cHCV), spontaneously resolved (rHCV), and subjects undergoing direct-acting antiviral (DAA) therapy.ResultsWe show that HCV-specific CD8+ T cells have cytotoxic features in patients with cHCV, which is progressively reduced with DAA therapy and persists 12 weeks after treatment completion. We also observe a shift in the CD8+ T cell phenotype on DAA treatment, with decreased effector memory and exhausted cell signatures. In rHCV, we also detected a smaller proportion of effector memory cells compared to cHCV. The proportion of CD8+ exhausted T cells in cHCV and rHCV subjects was comparable. Moreover, we also observed that non-HCV virus-specific CD8+ T cells exhibit robust cytotoxic traits during cHCV infection.DiscussionAltogether, our findings suggest that cHCV infection promotes cytotoxicity in CD8+ T cells regardless of virus specificity. The immunological changes caused by cHCV infection in CD8+ T cells may contribute to worsening the ongoing hepatic damage caused by HCV infection or exacerbate the immune response to possible co-infections. Our data provide a resource to groups exploring the underlying mechanisms of HCV-specific T cell spontaneous and treatment-induced resolution to inform the development of effective vaccines against HCV infection

Etiology of end-stage liver cirrhosis impacts hepatic natural killer cell heterogenicity

The natural killer (NK) cell population is a critical component of the innate immune compartment of the liver, and its functions are deeply affected by the surrounding environment. In the late stage of fibrosis, NK cells become dysfunctional, but the influence of disease etiology on NK cell behavior during cirrhosis remains unclear. Using single-cell RNA sequencing (scRNA-seq), we characterized the hepatic NK cells from end-stage cirrhotic livers from subjects with non-alcoholic steatohepatitis (NASH), chronic hepatitis C infection (HCV) and primary sclerosing cholangitis (PSC). Here, we show that although NK cells shared similar dysfunctions, the disease etiology impacts hepatic NK cell heterogeneity. Therapeutical strategies targeting NK cells for the prevention or treatment of fibrosis should consider liver disease etiology in their design

T-Cell Dysfunction and Inhibitory Receptors in Hepatitis C Virus Infection

Dysfunction of the virus-specific T cells is a cardinal feature in chronic persistent viral infections such as one caused by hepatitis C virus (HCV). In chronic HCV infection, virus-specific dysfunctional CD8 T cells often overexpress various inhibitory receptors. Programmed cell death 1 (PD-1) was the first among these inhibitory receptors that were identified to be overexpressed in functionally impaired T cells. The roles of other inhibitory receptors such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) have also been demonstrated in T-cell dysfunctions that occur in chronic HCV patients. Blocking these inhibitory receptors in vitro restores the functions of HCV-specific CD8 T cells and allows enhanced proliferation, cytolytic activity and cytokine production. Therefore, the blockade of the inhibitory receptors is considered as a novel strategy for the treatment of chronic HCV infection