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.

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.

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.

Abstract 004: Aberrant CD4 + T Cell Function in Stroke-prone Hypertensive Rats Due to a Mutation in Stim1

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Isha S Dhande ◽  
Mykola Mamenko ◽  
Yaming Zhu ◽  
Oleh Pochynyuk ◽  
Scott Wenderfer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Production ◽  
Cell Function ◽  
Spontaneously Hypertensive Rat ◽  
Flow Cytometric Analysis ◽  
T Cell Subsets ◽  
Organ Injury ◽  
Truncating Mutation ◽  
T Cell Function

The genetic mechanism of end organ injury in hypertension may involve gene variation in genes participating in inflammation and its regulation. We identified a novel truncating mutation in the hypertensive end organ injury-prone spontaneously hypertensive rat (SHR-A3/SHRSP) line affecting the C-terminus of STIM1, a protein involved in the store-operated Ca 2+ entry (SOCE) pathway. The genomes of injury-resistant SHR lines, including SHR-B2 used here, encode the ‘wild-type’ STIM1. SOCE is required by T cells to activate the transcription factor NFAT and regulate T cell proliferation and cytokine production. T cell receptor (TCR) stimulation depletes intracellular Ca 2+ stores, activates the ER Ca 2+ -sensor STIM1 and results in SOCE. We tested the effect of STIM1 mutation on lymphocyte SOCE and found it was dramatically reduced in SHR-A3, but not in SHR-B2 (maximal [Ca 2+ ] i : 150.5±34.9 vs 521.5±42.6 nM, p<0.0001). Flow cytometric analysis of circulating T cell subsets revealed comparable levels of CD4 + and CD8 + T cells in both lines, however circulating CD4 + CD25 + FoxP3 + T regs were reduced in SHR-A3 compared to SHR-B2 (4.34±0.59 vs 7.12±0.33%, p=0.01). TCR-induced lymphocyte proliferation was similar in both SHR-A3 and SHR-B2. T cell cytokine production in response to TCR stimulation was markedly impaired CD4 + T cells from SHR-A3 compared with SHR-B2 (IL-2: 168 ±83.4 vs 1385±377.0 pg/mL, p=0.01; IFNγ: 235±69.5 vs 2119±434.7 pg/mL, p=0.002). IL-2 and IFNγ production was completely inhibited by Pyr6, an inhibitor of Stim1-dependent SOCE. However, circulating levels of IL-2 and IFNγ were not different between the two lines. Based on our findings, we conclude that TCR-mediated effector signaling is impaired due to defective SOCE in SHR-A3 rats. Defects in SOCE in SHR-A3 attributable to STIM1 mutation alter T cell function, reduce T reg numbers and may disturb regulatory interactions between T cells and other immune cells involved in end organ injury.

scholarly journals LXR directly regulates glycosphingolipid synthesis and affects human CD4+ T cell function

2021 ◽  
Vol 118 (21) ◽  
pp. e2017394118
Author(s):  
Kirsty E. Waddington ◽  
George A. Robinson ◽  
Beatriz Rubio-Cuesta ◽  
Eden Chrifi-Alaoui ◽  
Sara Andreone ◽  
...  
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
Lipid Metabolism ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Function ◽  
Cholesterol Metabolism ◽  
T Cell Subsets ◽  
Lipid Order ◽  
T Cell Function

The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here, we explored the role of LXR-regulated metabolic processes in primary human CD4+ T cells and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol), which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened proinflammatory T cell function. Finally, compared with responder T cells, regulatory T cells had a distinct pattern of LXR target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism and demonstrate its relevance in modulating T cell function.

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.

Phase IIa study of marrow infiltrating lymphocytes (MILs), an adoptive T cell therapy, alone or in combination with nivolumab in non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9630-TPS9630
Author(s):  
Martin Edelman ◽  
Aaron Elliott Lisberg ◽  
Marianna Koczywas ◽  
Ben C. Creelan ◽  
Amanda Seiz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Function ◽  
T Cell Subsets ◽  
Autologous Tumor ◽  
Secondary Resistance ◽  
Positive Effects ◽  
T Cell Function

TPS9630 Background: Primary or secondary resistance to anti-PD-1 may be due to loss of T cell function. Persistent antigen stimulation can lead to impaired CD8+ T cell function, which often results in acquired resistance to PD-1 inhibition. It is unclear whether reinvigoration of tumor infiltrating cells or recruitment of novel T cells impart the activity of anti-PD-1 therapy. The bone marrow is a reservoir for antigen experienced memory T cells. We have previously shown that MILs can be generated for patients with hematologic malignancies and solid tumors including patients with NSCLC. MILs are the product of the activation and expansion of bone marrow T cells with a polyantigenic memory phenotype that recognize tumor antigens, are cytotoxic to autologous tumor and are able to persist over a long period of time. In a pre-clinical study of NSCLC, MILs were able to be expanded in all patients tested. Furthermore, all of the NSCLC products tested showed specificity to shared NSCLC antigens. The combination of adoptive cell therapy (ACT) with checkpoint inhibitors (CPIs) has distinctive positive effects on CD8 and CD4 T cell subsets, with the possibility for complete tumor control. We hypothesize that patients with NSCLC who have relapsed on anti-PD-1 treatment could benefit from an infusion of non-exhausted, central memory-enhanced, antigen specific T cells i.e. MILs which can delay the induction of tumor-associated anergy and augment the overall effectiveness of immunotherapy. Methods: Patients with advanced NSCLC who have progressed following prior anti-PD-1 therapy, with sufficient bone marrow reserve and an ECOG 0-1 are eligible. In eligible patients, bone marrow (200 mL) will be harvested and processed. Patients will undergo lymphodepletion (fludarabine 300 mg/m2/day and cyclophosphamide 30 mg/m2/day on days -5,-4,-3) followed by infusion of MILs on day 0. In Part 1, up to 6 patients will be administered MILs alone on day 0. In Part 2, approximately 20 subjects will be administered MILs on day 0 followed by NIVO 480 mg Q4W starting on day 1. The objectives of the study are to assess safety of MILs alone and in combination with NIVO, as well as efficacy. The first patient was treated in December 2019. Clinical trial information: NCT04069936 .

scholarly journals Reversal of the CD8+ T-Cell Exhaustion Induced by Chronic HIV-1 Infection Through Combined Blockade of the Adenosine and PD-1 Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Li ◽  
Hui-Huang Huang ◽  
Bo Tu ◽  
Ming-Ju Zhou ◽  
Wei Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cell Function ◽  
T Cell Subsets ◽  
Cell Counts ◽  
T Cell Function ◽  
Treatment Naïve ◽  
Hiv 1

BackgroundTargeting immune checkpoints for HIV treatment potentially provides a double benefit resulting from the ability to restore viral-specific CD8+ T-cell functions and enhance HIV production from reservoir cells. Despite promising pre-clinical data, PD-1 blockade alone in HIV-1-infected patients with advanced cancer has shown limited benefits in controlling HIV, suggesting the need for additional targets beyond PD-1. CD39 and PD-1 are highly co-expressed on CD8+ T cells in HIV-1 infection. However, the characteristics of CD39 and PD-1 dual-positive CD8+ T-cell subsets in chronic HIV-1 infection remain poorly understood.MethodsThis study enrolled 72 HIV-1-infected patients, including 40 treatment naïve and 32 ART patients. A total of 11 healthy individuals were included as controls. Different subsets of CD8+ T cells defined by CD39 and/or PD-1 expression were studied by flow cytometry. The relationships between the frequencies of the different subsets and parameters indicating HIV-1 disease progression were analyzed. Functional (i.e., cytokine secretion, viral inhibition) assays were performed to evaluate the impact of the blockade of adenosine and/or PD-1 signaling on CD8+ T cells.ResultsThe proportions of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells were significantly increased in treatment naïve patients but were partially lowered in patients on antiretroviral therapy. In treatment naïve patients, the proportions of PD-1+CD39+ CD8+ T cells were negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio, and were positively correlated with viral load. CD39+CD8+ T cells expressed high levels of the A2A adenosine receptor and were more sensitive to 2-chloroadenosine-mediated functional inhibition than their CD39- counterparts. In vitro, a combination of blocking CD39/adenosine and PD-1 signaling showed a synergic effect in restoring CD8+ T-cell function, as evidenced by enhanced abilities to secrete functional cytokines and to kill autologous reservoir cells.ConclusionIn patients with chronic HIV-1 infection there are increased frequencies of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells. In treatment naïve patients, the frequencies of PD-1+CD39+ CD8+ T cells are negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio and positively correlated with viral load. Combined blockade of CD39/adenosine and PD-1 signaling in vitro may exert a synergistic effect in restoring CD8+ T-cell function in HIV-1-infected patients.

scholarly journals LXR alters CD4+ T cell function through direct regulation of glycosphingolipid synthesis

2019 ◽  
Author(s):  
Kirsty E Waddington ◽  
George A Robinson ◽  
Beatriz Rubio-Cuesta ◽  
Eden Chrifi-Alaoui ◽  
Sara Andreone ◽  
...  
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
Lipid Metabolism ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Function ◽  
Cholesterol Metabolism ◽  
T Cell Subsets ◽  
Lipid Order ◽  
T Cell Function

AbstractThe liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here we explored the role of LXR-regulated metabolic processes in primary human CD4+ T cells, and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol) which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase (UGCG) as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened pro-inflammatory T cell function. Finally, compared to responder T cells, regulatory T cells had a distinct pattern of LXR-target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a novel mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism, and demonstrate its relevance in modulating T cell function.

scholarly journals PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Renan Garcia de Moura ◽  
Luciana Polaco Covre ◽  
Carlos Henrique Fantecelle ◽  
Vitor Alejandro Torres Gajardo ◽  
Carla Baroni Cunha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cutaneous Leishmaniasis ◽  
Cell Function ◽  
Parasite Clearance ◽  
Skin Lesions ◽  
T Cell Subsets ◽  
Leishmania Braziliensis ◽  
T Cell Function

Patients infected by Leishmania braziliensis develop debilitating skin lesions. The role of inhibitory checkpoint receptors (ICRs) that induce T cell exhaustion during this disease is not known. Transcriptional profiling identified increased expression of ICRs including PD-1, PDL-1, PDL-2, TIM-3, and CTLA-4 in skin lesions of patients that was confirmed by immunohistology where there was increased expression of PD-1, TIM-3, and CTLA-4 in both CD4+ and CD8+ T cell subsets. Moreover, PDL-1/PDL-2 ligands were increased on skin macrophages compared to healthy controls. The proportions PD1+, but not TIM-3 or CTLA-4 expressing T cells in the circulation were positively correlated with those in the lesions of the same patients, suggesting that PD-1 may regulate T cell function equally in both compartments. Blocking PD-1 signaling in circulating T cells enhanced their proliferative capacity and IFN-γ production, but not TNF-α secretion in response to L. braziliensis recall antigen challenge in vitro. While we previously showed a significant correlation between the accumulation of senescent CD8+CD45RA+CD27- T cells in the circulation and skin lesion size in the patients, there was no such correlation between the extent of PD-1 expression by circulating on T cells and the magnitude of skin lesions suggesting that exhausted-like T cells may not contribute to the cutaneous immunopathology. Nevertheless, we identified exhausted-like T cells in both skin lesions and in the blood. Targeting this population by PD-1 blockade may improve T cell function and thus accelerate parasite clearance that would reduce the cutaneous pathology in cutaneous leishmaniasis.

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