scholarly journals Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer

2016 ◽  
Vol 64 (12) ◽  
pp. 753-767 ◽  
Author(s):  
Scott M. Tanner ◽  
Joseph G. Daft ◽  
Stephanie A. Hill ◽  
Colin A. Martin ◽  
Robin G. Lorenz
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cell Function ◽  
Interleukin 17 ◽  
Intestinal Tumor ◽  
Double Positive ◽  
Tumor Immunosurveillance ◽  
T Cell Function ◽  
Ifn Γ ◽  
Cell Balance

The adenomatous polyposis coli ( APC) gene is a known tumor suppressor gene, and mice with mutations in Apc (ApcMin/+) spontaneously form multiple intestinal neoplasms. In this model of human colorectal cancer (CRC), it has been reported that CD4+ T-cell-derived interleukin 17 (IL-17) promotes intestinal tumor development, but it is not known if the Apc mutation actually directly alters T-cell function and subsequently tumor immunosurveillance. To investigate the ApcMin/+ mutation on T-cell function, flow cytometric, histochemical, and immunofluorescent studies on both wild-type (Apc+/+) and ApcMin/+ mice were performed. We identified decreased levels of interferon gamma (IFN-γ+)IL-17+ double-positive CD4+ cells in the mesenteric lymph nodes and Peyer’s patches of ApcMin/+ mice. In addition, altered levels of CD8+ cells, and changes in CD8+ production of IFN-γ and granzyme B were observed. These T-cell alterations did modify tumor immunosurveillance, as the adoptive transfer of splenocytes from ApcMin/+ animals into a chemically induced CRC model resulted in the inability to prevent epithelial dysplasia. These results suggest an altered T-cell balance in ApcMin/+ mice may disrupt intestinal homeostasis, consequently limiting intestinal tumor immunosurveillance.

scholarly journals Modulation of PKM activity affects the differentiation of TH17 cells

2020 ◽  
Vol 13 (655) ◽  
pp. eaay9217
Author(s):  
Scott M. Seki ◽  
Kacper Posyniak ◽  
Rebecca McCloud ◽  
Dorian A. Rosen ◽  
Anthony Fernández-Castañeda ◽  
...  
Keyword(s):  
T Cell ◽  
Small Molecules ◽  
Th17 Cells ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Interleukin 17 ◽  
Gm Csf ◽  
T Cell Function ◽  
The Brain ◽  
Tgf Β1

Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell–mediated autoimmunity that mimics multiple sclerosis (MS). TH17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17–producing TH17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition, we found that activation of PKM2 interfered with TGF-β1 signaling, which is necessary for the development of TH17 and regulatory T cells. Collectively, our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function.

scholarly journals The Level of Viral Antigen Presented by Hepatocytes Influences CD8 T-Cell Function

2007 ◽  
Vol 81 (6) ◽  
pp. 2940-2949 ◽  
Author(s):  
Adam J. Gehring ◽  
Dianxing Sun ◽  
Patrick T. F. Kennedy ◽  
Esther Nolte-'t Hoen ◽  
Seng Gee Lim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Antigen ◽  
Cell Function ◽  
Cd8 T Cell ◽  
T Cell Function ◽  
Tnf Α ◽  
Antiviral Function ◽  
Ifn Γ

ABSTRACT CD8 T cells exert their antiviral function through cytokines and lysis of infected cells. Because hepatocytes are susceptible to noncytolytic mechanisms of viral clearance, CD8 T-cell antiviral efficiency against hepatotropic viruses has been linked to their capacity to produce gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). On the other hand, intrahepatic cytokine production triggers the recruitment of mononuclear cells, which sustain acute and chronic liver damage. Using virus-specific CD8 T cells and human hepatocytes, we analyzed the modulation of virus-specific CD8 T-cell function after recognition peptide-pulsed or virally infected hepatocytes. We observed that hepatocyte antigen presentation was generally inefficient, and the quantity of viral antigen strongly influenced CD8 T-cell antiviral function. High levels of hepatitis B virus production induced robust IFN-γ and TNF-α production in virus-specific CD8 T cells, while limiting amounts of viral antigen, both in hepatocyte-like cells and naturally infected human hepatocytes, preferentially stimulated CD8 T-cell degranulation. Our data document a mechanism where virus-specific CD8 T-cell function is influenced by the quantity of virus produced within hepatocytes.

scholarly journals Comparative Analysis of Mycobacterium Tuberculosis-Specific Antigens and T-Cell Mitogen-Stimulated Interferon Gamma Production in Hemodialysis Patients and Healthy Individuals

2020 ◽  
Author(s):  
Heechul Park ◽  
Ye Na Kim ◽  
Sung-Bae Park ◽  
Junseong Kim ◽  
Jaewon Lim ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Gamma ◽  
Cell Function ◽  
Specific Antigen ◽  
Clinical Manifestations ◽  
Hemodialysis Patients ◽  
Healthy Individuals ◽  
T Cell Function ◽  
Ifn Γ ◽  
Cell Mitogen

Abstract Background: The incidence of Tuberculosis (TB) is higher in patients undergoing chronic hemodialysis than in the general population; further, both the incidence and development of active TB from latent TB infection (LTBI) are considerably higher in patients undergoing hemodialysis than in any other group. The QuantiFERON-TB Gold In-Tube (QFT-GIT) assay is one of the most commonly used interferon gamma (IFN-γ) release assays (IGRAs) currently. We aim to know T-cell function of hemodialysis patients and the possible QFT false negatives.Methods: In order to analyze the MTB-specific antigen-stimulated IFN-γ release in patients on hemodialysis, the QFT-GIT test was used in this study. A total of 84 hemodialysis patients and 52 healthy subjects were enrolled from Kosin University Gospel Hospital and Catholic University of Pusan, Busan, Republic of Korea; their whole blood samples were collected and used for the present study.Results: The positivity results of the IGRAs in hemodialysis patients and normal subjects were 34/84 (40.4%) and 4/52 (7.6%), respectively. The median value of MTB-specific antigen-stimulated IFN-γ in hemodialysis patients with LTBI and non-LTBI status in hemodialysis patients, healthy individuals were 1.85 IU/mL (4.44ng/mL) and 0.028 IU/mL (0.067 ng/mL) and 0.255 IU/mL (0.612 ng/mL) respectively. In addition, Of the 34 LTBI status in hemodialysis patients, 14 (41.2%) had T-cell mitogen-stimulated IFN-γ levels of 10 or less, and 20 (58.8%) had 10 or more T-cell mitogen-stimulated IFN-γ. Moreover, Of the 49 non-LTBI status in hemodialysis patients, 19 (38.8%) and 30 (61.2%) respectively. On the other hand, there was no low level of T-cell mitogen-stimulated IFN-γ in the healthy individuals.Conclusion: This reveals that T-cell function in hemodialysis patients was reduced as compared to the healthy individuals. Therefore, the cut-off value should be adjusted for the active TB high-risk group when using IGRA tests. The clinical manifestations of TB in patients on hemodialysis are quite non-specific, making timely diagnosis difficult, and delaying the initiation of curative treatment, delay being a major determinant of outcome.

scholarly journals Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients

2011 ◽  
Vol 41 (8) ◽  
pp. 2314-2322 ◽  
Author(s):  
Qiyi Zhao ◽  
Xiao Xiao ◽  
Yan Wu ◽  
Yi Wei ◽  
Ling-Yan Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Cell Function ◽  
Cytotoxic T Cell ◽  
Interleukin 17 ◽  
T Cell Function

scholarly journals Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma: CALGB 500104

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8014-8014 ◽  
Author(s):  
T. F. Gajewski ◽  
D. Niedzwiecki ◽  
J. Johnson ◽  
G. Linette ◽  
C. Bucher ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
T Cell Activation ◽  
Cell Function ◽  
Immunosuppressive Agents ◽  
Single Agent ◽  
Clinical Activity ◽  
Combination Therapies ◽  
T Cell Function ◽  
Ifn Γ

8014 Background: Ras-based signaling is thought to be critical in the genesis of melanoma. Farneslytransferase (FT) inhibitors (FTIs) have been developed as a pharmacologic strategy to inhibit Ras function. Additional farnesylated proteins are also important for the malignant process, and FTIs inhibit melanoma cell line proliferation in vitro. These considerations motivated the development of a phase II trial of the FTI R115777 in patients with melanoma. Farnesylated proteins are also important for T cell activation. The interest in future combinations of targeted agents and immunotherapeutics in this disease prompted analysis of T cell function ex vivo. Methods: A 3-stage design was pursued with a maximum of 40 patients planned and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included intact organ function, PS≤1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to excisional biopsy. R115777 (300 mg orally) was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST criteria. Blood was obtained pre-treatment and during week 7 for analysis of HDJ-2 farnesylation and for T cell IFN-γ production in response to SEA. In addition, tumor biopsies were performed pre- and post-treatment when feasible to directly measure FT activity. Results: 14 patients were enrolled. 2 patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses, and only 4 patients went on to a second course of treatment. All analyzed patients showed HDJ-2 gel shift in peripheral blood cells, as well as marked inhibition of FT activity (by 85–98%) in tumor tissue. T cell production of IFN-γ was also suppressed. Conclusions: Despite potent target inhibition, the FTI R115777 showed no evidence for clinical activity as a single agent in this cohort of 14 metastatic melanoma patients. Inhibition of T cell function has implications for future combination therapies and suggests the possibility for FTIs as candidate immunosuppressive agents. New therapeutic approaches for melanoma, or logically selected combination therapies, are needed. [Table: see text]

PD-1 Protects Liver Damage by Suppressing IFN-γ Expression in T Cells in Infants and Neonatal Mice

2021 ◽  
Author(s):  
Xuangjie Guo ◽  
Yiping Xu ◽  
Wei Luo ◽  
Li Cai ◽  
Ping Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Protective Role ◽  
Control Subjects ◽  
T Cell Function ◽  
Ifn Γ ◽  
And Control

Abstract Background: Biliary atresia (BA) is a severe cholangiopathy resulting from virus-induced and immune-mediated injury of the biliary system. IFN-g, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death 1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. Methods: Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. Results: PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver. Blockade of PD-1 increased IFN-g expression in CD4+ T and CD8+ T cells, suppressed bilirubin production and exacerbated liver immunopathology.Conclusions: PD-1 plays a protective role in infants with BA by suppressing IFN-g production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.

ARID1A mutation to define an immunologically active subgroup in patients with microsatellite-stable colorectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 215-215
Author(s):  
Amir Mehrvarz Sarshekeh ◽  
Jason Roszik ◽  
Ganiraju C. Manyam ◽  
Shailesh M. Advani ◽  
Jason Willis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Immune Checkpoint ◽  
Cell Function ◽  
Immune Therapy ◽  
Silent Mutation ◽  
Cytotoxic T Cell ◽  
Wild Type ◽  
Frame Shift ◽  
Ifn Γ

215 Background: AT-rich interactive domain 1A (ARID1A) is a chromatin regulator mutated in human cancers, frequently resulting in truncation and loss of expression of this protein. ARID1A recruits MSH2 during DNA replication to perform mismatch-repair. ARID1A deficiency has been shown to increase mutational load and immune activation in preclinical models (Shen J, Nat Med 2018) but its role in colorectal cancer (CRC) patients (pts) is being explored. Methods: The DNA sequencing and gene expression profiling of microsatellite-stable (MSS) CRC pts were extracted from TCGA and MD Anderson Cancer Center databases. The expression levels were normalized according to the mean values of each dataset. The mutational burden and expression signatures for IFN-γ and various immune markers were compared according to the ARID1A mutational status. Results: Among 417 pts with MSS CRC, 28 pts (6.7%) had a non-silent mutation in ARID1A. Out of the 58 genes most commonly mutated in CRC, non-silent mutation in ARID1A had the strongest association with the frame-shift mutation rate in MSS cases (8-fold increase, p< .001). ARID1A mutation had also a strong correlation with the IFN-γ expression signature in MSS CRC (Δz score +1.91, p< .001) . Compared with ARID1A wild-type pts, higher expression signatures for cytotoxic T cell function, NK cells, and immune checkpoints were observed in MSS ARID1A mutated cases. ARID1A mutant cases showed higher expressions of various immune checkpoint genes (CD274, CTLA4, HAVCR2, IDO1, LAG3, PDCD1, and PDCD1LG2) compared to wild-type cases (all p < .05). All findings were observed independently in both datasets. Conclusions: In MSS CRC, ARID1A mutation is associated with a high expression of IFN-γ pathway and immune signatures (such as cytotoxic T cell function and immune checkpoint markers). The immunogenicity of ARID1A mutant cases is likely due to the increased level of neoantigens resulting from the increased rate of frame-shift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should likely be recognized as a unique molecular subgroup in future immune therapy trials.

scholarly journals Chlamydia muridarum T-Cell Antigens Formulated with the Adjuvant DDA/TDB Induce Immunity against Infection That Correlates with a High Frequency of Gamma Interferon (IFN-γ)/Tumor Necrosis Factor Alpha and IFN-γ/Interleukin-17 Double-Positive CD4+ T Cells

2010 ◽  
Vol 78 (5) ◽  
pp. 2272-2282 ◽  
Author(s):  
Hong Yu ◽  
Xiaozhou Jiang ◽  
Caixia Shen ◽  
Karuna P. Karunakaran ◽  
Janina Jiang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 17 ◽  
Double Positive ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
T Cell Antigens ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Major impediments to developing a Chlamydia vaccine lie in identifying immunologically relevant T-cell antigens and delivery in a manner to stimulate protective immunity. Using an immunoproteomic approach, we previously identified three immunodominant Chlamydia T-cell antigens (PmpG-1, PmpE/F-2, and RplF). Because RplF has high homology to a human ortholog, it may not be suitable for human vaccine development. Therefore, in this study, we evaluated protection against Chlamydia infection in the genital tract in C57BL/6 mice immunized with Chlamydia-specific membrane proteins PmpG-1, PmpE/F-2, and major outer membrane protein (MOMP; as a reference) or a combination of them formulated with one of three adjuvants, CpG oligodeoxynucleotide (CpG-ODN), AbISCO-100 (AbISCO), or DDA/TDB (dimethyldioctadecylammonium bromide/d-(+)-trehalose 6,6′-dibehenate). The results show that immunization with the CpG-ODN formulation failed to provide protection against Chlamydia infection; the AbISCO formulation conferred moderate protection, and the DDA/TDB formulation showed the highest degree of protective efficacy. The combination of PmpG-1, PmpE/F-2, and MOMP proteins formulated with DDA/TDB exhibited the greatest degree of protection among all vaccine groups studied. Moreover, this vaccine combination also engendered significant protection in BALB/c mice, which have a different major histocompatibility complex (MHC) background. We measured cell-mediated immune cytokine responses in mice immunized with PmpG-1 mixed with each of the three adjuvants. The results demonstrate that mice immunized with the DDA/TDB formulation induced the strongest gamma interferon (IFN-γ) and interleukin-17 (IL-17) responses, characterized by the highest frequency of IFN-γ/tumor necrosis factor alpha (TNF-α) and IFN-γ/IL-17 double-positive CD4+ T cells. In conclusion, a Chlamydia vaccine based on the recombinant proteins PmpG-1, PmpE/F-2, and MOMP delivered in a DDA/TDB adjuvant conferred protection against infection that correlated with IFN-γ/TNF-α and IFN-γ/IL-17 double-positive CD4+ T cells.

scholarly journals Programmed cell death protein-1 (PD-1) protects liver damage by suppressing IFN-γ expression in T cells in infants and neonatal mice

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuangjie Guo ◽  
Yiping Xu ◽  
Wei Luo ◽  
Rongli Fang ◽  
Li Cai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Protective Role ◽  
Control Subjects ◽  
T Cell Function ◽  
Ifn Γ ◽  
And Control

Abstract Background Biliary atresia (BA) is a severe cholangiopathy possibly resulting from virus-induced and immune-mediated injury of the biliary system. IFN-γ, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death protein-1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. Methods Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. Results PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver (PD-1+CD4+T cells in liver vs. IFN-γ concentration, r = − 0.25, p = 0.05; PD-1+CD8+T cells in liver vs. IFN-γ concentration, r = − 0.39, p = 0.004). Blockade of PD-1 increased IFN-γ expression in CD4+ T and CD8+ T cells (RRV vs. anti-PD-1 treated RRV mice: 11.59 ± 3.43% vs. 21.26 ± 5.32% IFN-γ+ in hepatic CD4+T cells, p = 0.0003; 9.33 ± 4.03% vs. 22.55 ± 7.47% IFN-γ+ in hepatic CD8+T cells, p = 0.0001), suppressed bilirubin production (RRV vs. anti-PD-1 treated RRV mice: 285.4 ± 47.93 vs. 229.8 ± 45.86 μmol/L total bilirubin, p = 0.01) and exacerbated liver immunopathology. Conclusions PD-1 plays a protective role in infants with BA by suppressing IFN-γ production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.

T-Cell Function in Patients with B-Cell Chronic Lymphocytic Leukemia (B-CLL) Following Alemtuzumab (Campath®) or Fludarabine Treatment.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2513-2513
Author(s):  
Shahryar Kiaii ◽  
Fariba Mozaffari ◽  
Jeanette Lundin ◽  
Reza Rezvany ◽  
Aniruddha Chudhury ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Proliferative Response ◽  
Cell Function ◽  
T Cell Subsets ◽  
Control Group ◽  
Antitumor Effects ◽  
T Cell Function ◽  
Increased Risk ◽  
Ifn Γ

Abstract Fludarabine and alemtuzumab (humanized anti-CD52 antibody, Campath®) are both used as routine therapy for patients with B-CLL. Fludarabine and in particular alemtuzumab, in addition to their antitumor effects, induce long-lasting suppression of T-cell numbers in blood. T-cell suppression, in combination with advanced disease, may result in an increased risk of opportunistic and other infections. In addition to a decrease in circulating T cells, functional defects in T cells have been described following alemtuzumab therapy for non-malignant disorders; however, only a limited amount of information exists about the effect of alemtuzumab on T-cell function in patients with B-CLL. The aim of the present study was to characterize in detail various aspects of T-cell function in patients with B-CLL who were in stable unmaintained PR or CR following fludarabine (n = 9) and alemtuzumab (n = 10) treatment as well as in age-matched healthy control donors (n = 10). CD4 and CD8 T-cell subsets of freshly obtained peripheral blood mononuclear cells (PBMC) were analyzed by flow cytometry to measure the expression of TCR-CD3 ζ chain, p56Lck, p59Fyn, ZAP-70, and PI3 Kinase as well as intracellular production of IFN-γ and IL-4. Additional analyses were performed to measure the proliferative response capability to a recall antigen (PPD) in alemtuzumab-treated patients and (as a control) indolent, untreated B-CLL patients (n = 11). The expression of IFN-γ and IL-4 (measured as mean fluorescence intensity [MFI]), but not the total number of positive cells, was significantly higher in CD4 and CD8 T cells for both CLL groups compared to healthy donors with the highest expression observed in alemtuzumab-treated patients. The total number of T cells that expressed the five signaling molecules was significantly lower in treated patients versus control donors; however, there were no differences between fludarabine- and alemtuzumab-treated patients. MFI analysis showed a significant increase in the TCR-CD3 ζ chain in fludarabine-treated patients compared to control donors; however, MFI analysis revealed no other significant differences between control group patients and fludarabine- and alemtuzumab-treated patients. Moreover, the proliferative response to PPD was not significantly different in alemtuzumab-treated patients and indolent CLL patients. In conclusion, these results suggest that the intrinsic signal transduction machinery in T cells is relatively well-preserved, such that T cells remain functionally intact following fludarabine or alemtuzumab therapy despite a marked reduction in their numbers. These results provide a better understanding of the immune suppression induced by alemtuzumab and fludarabine therapy in B-CLL patients.

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