Proliferation and Activation Patterns of Naïve, Memory and Regulatory T Cells in Patients with Multiple Myeloma During Thalidomide, Interferon-α and Bortezomib Maintenance Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3880-3880
Author(s):  
Michael Hundemer ◽  
Isabelle Herth ◽  
Tobias Meissner ◽  
Dirk Hose ◽  
Anthony D Ho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Regulatory T Cells ◽  
Maintenance Therapy ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Granzyme B ◽  
Effector Memory ◽  
Control Group ◽  
Ifn Γ

Abstract Abstract 3880 Poster Board III-816 Hundemer and Herth (Contributed equally) Introduction In patients with Multiple myeloma, maintenance therapy after high-dose chemotherapy and autologous stem cell transplantation is performed with the aim to prolong remission duration and survival. Beside IFN-α, thalidomide and bortezomib are increasingly applied in maintenance protocols. In this prospective study we have analysed the implication of the various types of maintenance therapy on the patients T cell pattern and activation status. Patients and Methods T cells from 63 patients in clinical remission were analyzed. The median duration of remission was 38,6 months. Eighteen patients were treated with IFN-α, 22 with thalidomide, 7 with bortezomib and 16 patients received no maintenance therapy (control group). Peripheral blood mononuclear cells were isolated and stimulated with CD3/CD28 beads. Activated and nonactivated T cells were analyzed by flow cytometry (CD45RA, CD45RO, CCR7, CD28, CD200R, CD95, CD279, CD69, CD134 and TCRγ/δ) and ELISA (IFN-γ, perforine and granzym B). Furthermore the rate of IFN-γ-producing and regulatory T cells were analyzed by intracytoplasmatic staining and flow cytometry. Results All groups including the control group showed an up-regulation of CD69 and CD134 on CD4+ and CD8+ T cells after activation (p<0,001), on CD8+ T cells in the bortezomib-group only CD69 was upregulated (p=0,008). Patients treated with IFN-α showed a high rate of naïve T cells (CD45RA- and CCR7-positive), while in the thalidomide-group a high rate of effector memory T-cells (CD45RA- and CCR7-negative) were observed (CD45RA on CD8+ and CD4+ T cells: p<0,001, CCR7 on CD8+ T cells: p=0,03, CCR7 on CD4+ T cells: p=0,003). Regarding the surface marker CD28 on CD8+ T cells the IFN-α-group demonstrated a significant higher expression than the control-group (p=0,04) and the bortezomib-group a significant lower expression than the IFN-α- and the thalidomide-group (p=0,006 and p=0,02). Furthermore the rate of IFN-γ-producing CD4+ T cells was significant higher in the thalidomide-group than in the IFN-α-group after activation (p=0,02). On the basis of the cytoplasmatic staining of Foxp3 there was a trend to a higher amount of regulatory T cells in the thalidomide-group compared to the IFN-α-group (p=0,07). Analysis of IFN-y secretion by ELISA, an increases IFN-γ secretion could be demonstrated in all groups after activation (control group: p=0,002, IFN-α-group: p<0,001, thalidomide-group: p<0,001, bortezomib group: p=0,01), furthermore in all groups despite the bortezomib-group an increase of the granzyme B-production can be observed (control group: p=0,003, IFN-α-group: p=0,03, thalidomide-group: p<0,001). Regarding the activated state of the T cells the production of IFN-γ, perforine and granzyme B was significant higher in the thalidomide-group than in the IFN-α-group (IFN-γ: p=0,05, perforine: p=0,02, granzyme B: p=0,04). Furthermore the nonactivated and the activated T cells of the patients treated with thalidomide showed a significant higher production of granzyme B than the T cells of the control group (p=0,0003 and p=0,006). Conclusion During maintenance therapy, thalidomide promotes maturation and proliferation of effector memory T cells and regulatory T cells, while IFN-α treatment increases the number of naïve T cells and subsequently, the T cell activation in the thalidomide group was significantly higher than in the IFN-α group. These results have profound impact on the development of novel immunomodulating therapy strategies in the treatment of multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Expression of the Butyrate/Niacin Receptor, GPR109a on T Cells Plays an Important Role in a Mouse Model of Graft Versus Host Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 61-61 ◽  
Author(s):  
Melissa D Docampo ◽  
Christoph K. Stein-Thoeringer ◽  
Amina Lazrak ◽  
Marina D Burgos da Silva ◽  
Justin Cross ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Effector Memory ◽  
Knock Out ◽  
Graft Versus Host

Abstract INTRODUCTION: The intestinal microbiota is essential for the fermentation of fibers into the short-chain fatty acids (SCFA) butyrate, acetate and propionate. SCFA can bind to G-protein-coupled receptors GPR41, GPR43 and GPR109a to activate downstream anti-inflammatory signaling pathways. In colitis or graft versus host disease (GVHD), GPR43 signaling has been reported as an important regulator of intestinal homeostasis by increasing the pool of regulatory T cells. In contrast to GPR43, which binds preferentially propionate and acetate, GPR109a is the major receptor for butyrate. We and others have demonstrated that butyrate can ameliorate gastrointestinal injury during GVHD through enterocyte protection. Therefore, we hypothesized that GPR109a plays an important role in the pathophysiology of intestinal GVHD, focusing specifically on alloreactive T cells. METHODS AND RESULTS: Using mouse models of GVHD, we examined the role of the butyrate/niacin receptor, GPR109a in allogeneic hematopoietic cell transplantation (allo-HCT). First, we studied whether a genetic knock-out (KO) of GPR109a in transplant recipient mice affected GVHD, but GPR109a-KO recipient mice did not exhibit increased mortality from GVHD compared to wild type (WT) mice. We next investigated the role of GPR109a in the donor compartment by transplanting either BM or T cells from WT or GPR109a-KO mice into major MHC mismatched BALB/c host mice. Mice transplanted with B6 BM, with T cells from a GPR109a-KO mouse into BALB/c hosts displayed a lower incidence of lethal GVHD (Fig. 1A). To determine whether the attenuation of GVHD is intrinsic to GPR109a-KO T cells, we established BM chimeras and performed a secondary transplant by transplanting B6 BM + (B6 à Ly5.1) or (GPR109a à Ly5.1) T cells into BALB/c hosts. We observed the same improvement in survival in mice that received GPR109a-KO T cells. This indicates an intrinsic role for GPR109a specifically in the donor hematopoietic compartment. Having identified a T-cell specific requirement for GPR109a we next examined expression of GPR109a on WT T cells in vitro at baseline and following stimulation with CD3/28 and found GPR109a significantly upregulated on both CD4+ and CD8+ T cells after 72 hours of stimulation (Fig 1B). At steady state in vivo, we observed the same numbers and percentages of splenic effector memory, central memory, and naïve CD4+ T cells as well as regulatory T cells in WT B6 mice and GPR109a-KO mice, suggesting normal T cell development in the knockout mice. In an in vitro mixed lymphocyte reaction (MLR), GPR109a-KO CD4+ T cells become activated, proliferate, polarize and secrete cytokine (specifically IFNg) to the same level as WT CD4+ T cells, suggesting normal functional capacity. However, after allo-HCT in mice we observed significantly fewer CD4+ and CD8+ T cells, and specifically fewer effector memory CD4+ T cells (Fig. C), in the small and large intestines of mice that received GPR109a-KO T cells at day 7 post transplant. In contrast, we found significantly more regulatory T cells in the intestines (Fig. 1D) and the spleen of GPR1091-KO T cell recipients, while numbers and percentages of polarized Th1 and Th17 T cells were similar between the two groups. We further 16S rRNA sequenced the gut microbiota of mice at day 7 after transplant and observed an increased relative abundance of bacteria from the genus Clostridium (Fig. 1D) along with an increased concentration of cecal butyrate as measured by GC-MS (Fig. 1E). In a preliminary graft versus tumor (GVT) experiment, we found that mice that received A20 tumor cells and GPR109a-KO T cells exhibited increased survival compared to mice that received A20 tumor cells and WT T cells. These preliminary findings suggest that GPR109a-KO T cells maintain their graft versus tumor response while causing less GVHD, and exclude a defective functional capacity. CONCLUSIONS: We report a novel role of the butyrate/niacin receptor GPR109a on donor T cells in allo-HCT as a genetic knock-out on T cells attenuates lethal GVHD. As these T cells are tested as functionally intact, we propose that the reduction in overall T cells of KO T cell recipients may underlie the attenuation in GVHD. Furthermore, such a reduction in allograft-induced gut injury is accompanied by maintenance of the gut commensal Clostridium and butyrate production, which is known to protect the intestinal epithelium and increases the regulatory T cell pool. Disclosures No relevant conflicts of interest to declare.

Altered Expression of Functional Proteins in CD4 Regulatory T Cells during Therapy with Idelalisib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1735-1735 ◽  
Author(s):  
Tiago R Matos ◽  
Benjamin L Lampson ◽  
Masahiro Hirakawa ◽  
Siddha Kasar ◽  
Stacey M. Fernandes ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Drug Exposure ◽  
Cell Surface Expression ◽  
Effector Memory ◽  
Functional Markers ◽  
Altered Expression ◽  
And Function

Abstract Introduction: Idelalisib, a specific small molecule inhibitor of the delta isoform of PI3 kinase (PI3Kd), has recently been FDA approved for the treatment of relapsed CLL. Expression of PI3Kd is predominantly restricted to leukocytes, and inhibition of PI3Kd promotes apoptosis of neoplastic CLL cells. Patients who receive idelalisib often experience toxicities that appear to be immune mediated. In an ongoing phase II study of idelalisib-ofatumumab at DFCI, 16 of 21 patients experienced grade 3 or greater autoimmune toxicities (14 transaminitis, 2 enteritis/colitis and 3 presumed drug-induced pneumonitis). Methods: To identify potential causes of autoimmunity in patients receiving idelalisib, we used single cell mass cytometry (CyTOF) with a panel of 26 surface membrane and 9 intracellular markers to provide a comprehensive phenotypic and functional analysis of all peripheral blood lymphocytes. Blood samples were obtained at baseline prior to therapy and at onset of autoimmune symptoms, which occurred at a median of 28 days from start of therapy. Results in 5 severely affected patients were compared with 3 patients who did not develop autoimmune toxicities and 15 healthy donors. The second sample from unaffected patients was matched in time to the affected patient samples. Results: Within CD3 T cells, idelalisib therapy led to an increased percentage of CD4 T cells and decreased percentage of CD8 T cells. Within CD4 T cells, CD25high Foxp3+ regulatory T cells (Treg) were reduced, resulting in a marked increase of the ratio of conventional CD4 T (Tcon)/Treg and increased CD8/Treg ratio. These findings were similar in patients who developed autoimmune toxicities and those who did not. Analysis of effector memory (EM; 45RA- CCR7-), central memory (CM; 45RA- CCR7+), terminal effector (TEMRA; 45RA+ CCR7-) and naive (45RA+ CCR7+) subsets within Treg, Tcon and CD8 T cells was comparable before and after idelalisib therapy and with healthy individual controls. To evaluate the heterogeneity of each population we utilized viSNE, which allows visualization of complex high-dimensional cytometry data on a two-dimensional plot. Treg in patients who developed autoimmune phenomena were compared with Treg from patients who did not. In patients who developed autoimmunity, baseline Treg had higher expression of PD-1 and lower expression of functional markers, such as GITR, Tbet, CXCR3, PDL-1, granzyme-β and TIM-3. In some cases, expression of these functional markers declined further with idelalisib therapy (Figure 1). Cytotoxic T lymphocyte antigen 4 (CTLA4) is constitutively expressed by Treg, and its deficiency has been shown to limit suppressive function of Treg. Inducible co-stimulator (ICOS) also mediates the suppressive functions of CD4 Treg by regulating cell surface expression of CTLA-4. Interestingly, expression of CTLA-4 and ICOS did not change during idelalisib therapy (Figure 1). Susceptibility to apoptosis was monitored by expression of pro-survival Bcl-2 and pro-apoptotic CD95 (FAS). Treg from patients developing autoimmunity expressed lower levels of Bcl-2 and higher levels of CD95 compared to those who did not. Conversely, Treg of non-affected patients retained higher expression of functional markers and became more active, assessed by increased expression of HLA-DR. The use of CyTOF combined with our comprehensive panel allowed us to delineate up to 13 distinct Treg sub-populations among healthy controls. In contrast, CLL patients often lacked such broad Treg heterogeneity. Expression of functional markers by Tcon and CD8 T cells from patients who would develop side effects, were also slightly lower, suggesting that autoimmune toxicities were not due to expansion or activation of CD8 or Tcon effector cells but due to the defect in both number and function of Tregs, which became insufficient to maintain the immune tolerance. Conclusion: These studies allowed us to identify defects in both Treg number and function, which may be responsible for the autoimmune toxicities in patients receiving idelalisib therapy. Further studies may allow the development of a reliable predictor of these toxicities by evaluation of the Treg markers prior to drug exposure which could be used to guide therapy. Moreover, the identification of idelalisib as a Treg inhibitor suggests that it could be used as an immunomodulatory agent to target the Treg pathway, in patients with solid tumors. Disclosures No relevant conflicts of interest to declare.

A Novel Dendritic Cell-Derived Vaccine in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4484-4484
Author(s):  
Rebecca Karp Leaf ◽  
Dina Stroopinsky ◽  
Athalia Rachel Pyzer ◽  
Ada M. Kruisbeek ◽  
Sandra Van Wetering ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Granzyme B ◽  
Autologous Tumor ◽  
Facs Analysis ◽  
Ifn Γ ◽  
Antigen Presenting

Abstract Introduction: Despite recent advances in the treatment of multiple myeloma (MM), curative outcomes remain elusive with standard therapies. MM is characterized by immune dysregulation and a loss of tumor-associated T cell surveillance contributing to disease evolution. Cancer vaccines have emerged as a promising immunotherapeutic strategy that seeks to reestablish anti-tumor immunity through the effective presentation of tumor associated antigens in the context of positive costimulation and activation signals. DCOne is a cell based tumor vaccine derived from an acute myelogenous leukemia cell line, differentiated toward a dendritic cell (DC) phenotype (DCPrime, Netherlands). DCOne strongly expresses WT-1, PRAME, RHAMM, survivin, and MUC-1. Since MM cells commonly express these tumor-associated antigens as well, we explored the efficacy of DCOne in inducing myeloma-specific immunity. Methods/Results: We first investigated the capacity of DCOne to polarize T cells toward an activated phenotype. Peripheral blood mononuclear cells (PBMCs) derived from MM patients were cultured in the presence or absence of DCOne and pulsed with whole cell DCOne lysate 24 hours prior to analysis. Intracellular levels of IFN-γ and perforin in CD8+ T cells and intracellular levels of IL-10 in CD4+ T cells were assessed via FACS analysis. Following 10 days of co-culture, we observed an increased percentage of CD8+ IFN-γ+ T cells and an increased percentage of CD8+ perforin+ T cells in PBMCs co-cultured with DCOne versus those not co-cultured with DCOne (10.8% versus 3.3%, p=0.02, n=11 and 6.6% versus 1.7%, p=0.045, n=10, respectively). In contrast, exposure of PBMCs to DCOne did not alter the percentage of CD4+ IL-10+ T cells (p=0.53, n=8). Given the observed increase in IFN-γ- and perforin-positive CD8+ T cells after co-culture of MM PBMCs with DCOne, we investigated whether CD8+ T cells co-cultured with DCOne exhibited enhanced killing of autologous tumor cells in a standard cytotoxic T lymphocyte (CTL) assay measuring Granzyme B activity by FACS analysis. DCOne potently induced CTL-mediated killing of autologous MM cells as determined by an increased percentage of CD8+ Granzyme B+ cells in stimulated versus control cells (27.4% versus 12.5%, p=0.05, n=3). We next investigated the mechanism of action by which DCOne elicited a MM-specific response. We postulated that the allogeneic cell line would induce immune activation in part through the transfer of antigen to PBMC-derived antigen presenting cells; these antigen presenting cells would in turn be capable of eliciting response via MHC restricted presentation of antigen to autologous T cell populations. Consistent with this hypothesis, we demonstrated that 32% of patient-derived PBMCs exhibited uptake of DCOne RNA following co-culture (n=3). Uptake of DCOne RNA by patient-derived PBMCs was completely abrogated with Transwell separation. Next, we examined how patient-derived PBMCs take up DCOne antigens. Using Western Blot analysis, we found that MUC-1 and survivin are expressed in extracellular vesicles (EVs) derived from DCOne lysate. Thus, we conclude that DCOne antigens are trafficked via EVs secreted by the DCOne parent cell, whereupon they are taken up by MM patient-derived PBMCs. Conclusion: In conclusion, when cultured in vitro with MM patient-derived PBMCs, DCOne results in increased IFN-γ- and perforin-positive CD8+ T cells, as well as induction of autologous tumor killing by these cells. DCOne RNA is taken up by MM patient-derived PBMCs and trafficked to the extracellular environment via EVs. DCOne demonstrates in vitro efficacy as an "off-the-shelf" strategy for stimulating MM-specific immunity. A clinical trial is being planned. Disclosures Kruisbeek: DCPrime: Employment, Other: Founder, CSO, and CEO of DCPrime. Van Wetering:DCPrime: Employment. Arnason:Gilead: Consultancy. Rosenblatt:DCPrime: Research Funding; BMS: Research Funding; Astex: Research Funding. Avigan:Astex: Research Funding; DCPrime: Research Funding.

HCA587 protein vaccine induces specific antitumor immunity mediated by CD4+ T-cells expressing granzyme B in a mouse model of melanoma

2020 ◽  
Vol 20 ◽  
Author(s):  
Weiming Yang ◽  
Weiheng Zhang ◽  
Xiaozhong Wang ◽  
Liming Tan ◽  
Hua Li ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Antitumor Effect ◽  
Granzyme B ◽  
Cell Subset ◽  
Cell Mediated Immunity ◽  
Protein Vaccine ◽  
Tumor Tissues ◽  
Wide Range ◽  
Ifn Γ

Background: The antigen HCA587 (also known as MAGE-C2), which is considered a cancer-testis antigen, exhibits upregulated expression in a wide range of malignant tumors with unique immunological properties, and may thus serve as a promising target for tumor immunotherapy. Objective: To explore the antitumor effect of the HCA587 protein vaccine and the response of humoral and cell-mediated immunity. Methods: The HCA587 protein vaccine was formulated with adjuvants CpG and and ISCOM. B16 melanoma cells were subcutaneously inoculated to C57BL/6 mice, followed by treatment with HCA587 protein vaccine subcutaneously. Mouse survival was monitored daily, and tumor volume was measured every 2 to 3 days. The tumor sizes, survival time and immune cells in tumor tissues were detected. And the vital immune cell subset and effector molecules were explored. Results: After treatment with HCA587 protein vaccine, the vaccination generated elicited significant immune responses, which delayed tumor growth and improved animal survival. The vaccination increased the proportion of CD4+ T cells expressing IFN-γ and granzyme B in tumor tissues. Depletion of CD4+T cells resulted in an almost complete abrogation of the antitumor effect of the vaccination, suggesting that the antitumor efficacy was mediated by CD4+ T cells. In addition, knockout of IFN-γ resulted in a decrease in granzyme B levels which were secreted by CD4+ T cells, and the antitumor effect was also significantly attenuated. Conclusion: The HCA587 protein vaccine may increase the levels of granzyme B expressed by CD4+ T cells, and this increase is dependent on IFN-γ, and the vaccine resulted in a specific tumor immune response and subsequent eradication of the tumor.

scholarly journals Circulating CD4 T cells elicited by endemic coronaviruses display vast disparities in abundance and functional potential linked to both antigen specificity and age

2021 ◽  
Author(s):  
Katherine A Richards ◽  
Maryah Glover ◽  
Jeremy C Crawford ◽  
Paul Thomas ◽  
Chantelle White ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Protective Immunity ◽  
Granzyme B ◽  
Antigen Specificity ◽  
Functional Potential ◽  
Membrane Envelope ◽  
Ifn Γ ◽  
Human Coronaviruses ◽  
Repeated Infections

Abstract Repeated infections with endemic human coronaviruses are thought to reflect lack of long-lasting protective immunity. Here, we evaluate circulating human CD4 T cells collected prior to 2020 for reactivity towards hCoV spike proteins, probing for the ability to produce IFN-γ, IL-2 or granzyme B. We find robust reactivity to spike-derived epitopes, comparable to influenza, but highly variable abundance and functional potential across subjects, depending on age and viral antigen specificity. To explore the potential of these memory cells to be recruited in SARS-CoV-2 infection, we examined the same subjects for cross-reactive recognition of epitopes from SARS-CoV-2 nucleocapsid, membrane/envelope, and spike. The functional potential of these cross-reactive CD4 T cells was highly variable, with nucleocapsid-specific CD4 T cells, but not spike-reactive cells showing exceptionally high levels of granzyme production upon stimulation. These results are considered in light of recruitment of hCoV-reactive cells into responses of humans to SARS-CoV infections or vaccinations.

scholarly journals The effect of Kefir on The Immune Response of Healthy Volunteers In Vitro

2017 ◽  
Vol 3 (2) ◽  
pp. 28
Author(s):  
Desie Dwi Wisudanti
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Healthy Volunteers ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Fermented Milk ◽  
Bioactive Components ◽  
Ifn Γ

Kefir is a functional foodstuff of probiotics, made from fermented milk with kefir grains containing various types of beneficial bacteria and yeast. There have been many studies on the effects of oral kefir on the immune system, but few studies have shown the effect of bioactive components from kefir (peptides and exopolysaccharides/ kefiran), on immune responses. The purpose of this study was to prove the effect of kefir supernatant from milk goat on healthy immune volunteer response in vitro. The study was conducted on 15 healthy volunteers, then isolated PBMC from whole blood, then divided into 5 groups (K-, P1, P2, P3 and P4) before culture was done for 4 days. The harvested cells from culture were examined for the percentage of CD4+ T cells, CD8+ T cells, IFN-γ, IL-4 using flowsitometry and IL-2 levels, IL-10 using the ELISA method. The results obtained that kefir do not affect the percentage of CD4+ T cells and CD8+ T cells. The higher the concentration of kefir given, the higher levels of secreted IFN- γ and IL-4, but a decrease in IL-2 levels. Significant enhancement occurred at levels of IL-10 culture PBMC given kefir with various concentrations (p <0.01), especially at concentrations of 1%. These results also show the important effects of kefir bioactive components on immune responses. The conclusion of this study is that kefir can improve the immune response, through stimulation of IL-10 secretion in vitro.

scholarly journals Interleukin-30 Suppresses Not Only CD4+ T Cells but Also Regulatory T Cells in Murine Primary Biliary Cholangitis

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1031
Author(s):  
Hung-Wen Chen ◽  
Chia-I. Lin ◽  
Ya-Hui Chuang
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Primary Biliary Cholangitis ◽  
Autoimmune Cholangitis ◽  
Liver Inflammation ◽  
Adeno Associated Virus ◽  
Cytokines And Chemokines ◽  
Ifn Γ

Primary biliary cholangitis (PBC) is a chronic liver autoimmune disease with augmented T helper (Th) 1 and corresponding cytokine IFN-γ immune responses. Using 2-octynoic acid (2-OA) coupled to OVA (2-OA-OVA)-induced mouse models of autoimmune cholangitis (inducible chemical xenobiotic models of PBC), our previous study demonstrated that overexpression of IFN-γ in the model mice enhanced liver inflammation upon disease initiation, but subsequently led to the suppression of chronic inflammation with an increase in interleukin-30 (IL-30) levels. In this study, we investigated whether IL-30 had an immunosuppressive function and whether it could be part of an immune therapeutic regimen for PBC, by treating model mice with murine IL-30-expressing recombinant adeno-associated virus (AAV-mIL-30). We first defined the effects of AAV-mIL-30 in vivo by administering it to a well-known concanavalin A (ConA)-induced hepatitis model of mice and found that AAV-mIL-30 reduced the numbers of activated CD25+CD4+ T cells and the levels of serum IFN-γ and IL-12. In autoimmune cholangitis, decreased numbers of activated CD4+ T cells and Foxp3+ regulatory T cells were noted in the mice treated with AAV-mIL-30 at 3 weeks after the 2-OA-OVA immunization. Treatment with IL-30 did not change the features of autoimmune cholangitis including autoantibodies, cell infiltration, and collagen deposition in the liver at 11 weeks of examination. However, increased levels of cytokines and chemokines were observed. These results suggest that IL-30 suppresses not only CD4+ T cells but also regulatory T cells. Additionally, the administration of IL-30 did not suppress liver inflammation in the murine model of PBC.

scholarly journals Early Response of CD8+ T Cells in COVID-19 Patients

2021 ◽  
Vol 11 (12) ◽  
pp. 1291
Author(s):  
Deni Ramljak ◽  
Martina Vukoja ◽  
Marina Curlin ◽  
Katarina Vukojevic ◽  
Maja Barbaric ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Mrna Expression ◽  
Cd8 T Cells ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Effector Memory ◽  
Healthy Controls ◽  
Ifn Γ

Healthy and controlled immune response in COVID-19 is crucial for mild forms of the disease. Although CD8+ T cells play important role in this response, there is still a lack of studies showing the gene expression profiles in those cells at the beginning of the disease as potential predictors of more severe forms after the first week. We investigated a proportion of different subpopulations of CD8+ T cells and their gene expression patterns for cytotoxic proteins (perforin-1 (PRF1), granulysin (GNLY), granzyme B (GZMB), granzyme A (GZMA), granzyme K (GZMK)), cytokine interferon-γ (IFN-γ), and apoptotic protein Fas ligand (FASL) in CD8+ T cells from peripheral blood in first weeks of SARS-CoV-2 infection. Sixteen COVID-19 patients and nine healthy controls were included. The absolute counts of total lymphocytes (p = 0.007), CD3+ (p = 0.05), and CD8+ T cells (p = 0.01) in COVID-19 patients were significantly decreased compared to healthy controls. In COVID-19 patients in CD8+ T cell compartment, we observed lower frequency effector memory 1 (EM1) (p = 0.06) and effector memory 4 (EM4) (p < 0.001) CD8+ T cells. Higher mRNA expression of PRF1 (p = 0.05) and lower mRNA expression of FASL (p = 0.05) at the fifth day of the disease were found in COVID-19 patients compared to healthy controls. mRNA expression of PRF1 (p < 0.001) and IFN-γ (p < 0.001) was significantly downregulated in the first week of disease in COVID-19 patients who progressed to moderate and severe forms after the first week, compared to patients with mild symptoms during the entire disease course. GZMK (p < 0.01) and FASL (p < 0.01) mRNA expression was downregulated in all COVID-19 patients compared to healthy controls. Our results can lead to a better understanding of the inappropriate immune response of CD8+ T cells in SARS-CoV2 with the faster progression of the disease.

scholarly journals Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3818-3827 ◽  
Author(s):  
Lis R. V. Antonelli ◽  
Yolanda Mahnke ◽  
Jessica N. Hodge ◽  
Brian O. Porter ◽  
Daniel L. Barber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Interferon Γ ◽  
Effector Memory ◽  
Hiv Patients ◽  
Inflammatory Syndrome

Abstract Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of antiretroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1+, HLA-DR+, and Ki67+ CD4+ T cells than patients without IRIS. Moreover, PD-1+ CD4+ T cells in IRIS patients expressed increased levels of LAG-3, CTLA-4, and ICOS and had a Th1/Th17 skewed cytokine profile upon polyclonal stimulation. Elevated PD-1 and Ki67 expression was also seen in regulatory T cells of IRIS patients. Furthermore, IRIS patients displayed higher serum interferon-γ, compared with non-IRIS patients, near the time of their IRIS events and higher serum interleukin-7 levels, suggesting that the T-cell populations are also exposed to augmented homeostatic signals. In conclusion, our findings indicate that IRIS appears to be a predominantly CD4-mediated phenomenon with reconstituting effector and regulatory T cells showing evidence of increased activation from antigenic exposure. These studies are registered online at http://clinicaltrials.gov as NCT00557570 and NCT00286767.

scholarly journals Complementary Dendritic Cell–activating Function of CD8+ and CD4+ T Cells

2002 ◽  
Vol 195 (4) ◽  
pp. 473-483 ◽  
Author(s):  
Robbie B. Mailliard ◽  
Shinichi Egawa ◽  
Quan Cai ◽  
Anna Kalinska ◽  
Svetlana N. Bykovskaya ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Class I ◽  
Chronic Infections ◽  
Cd40 Ligation ◽  
Activation Level ◽  
Tnf Α ◽  
Ifn Γ

Dendritic cells (DCs) activated by CD40L-expressing CD4+ T cells act as mediators of “T helper (Th)” signals for CD8+ T lymphocytes, inducing their cytotoxic function and supporting their long-term activity. Here, we show that the optimal activation of DCs, their ability to produce high levels of bioactive interleukin (IL)-12p70 and to induce Th1-type CD4+ T cells, is supported by the complementary DC-activating signals from both CD4+ and CD8+ T cells. Cord blood– or peripheral blood–isolated naive CD8+ T cells do not express CD40L, but, in contrast to naive CD4+ T cells, they are efficient producers of IFN-γ at the earliest stages of the interaction with DCs. Naive CD8+ T cells cooperate with CD40L-expressing naive CD4+ T cells in the induction of IL-12p70 in DCs, promoting the development of primary Th1-type CD4+ T cell responses. Moreover, the recognition of major histocompatibility complex class I–presented epitopes by antigen-specific CD8+ T cells results in the TNF-α– and IFN-γ–dependent increase in the activation level of DCs and in the induction of type-1 polarized mature DCs capable of producing high levels of IL-12p70 upon a subsequent CD40 ligation. The ability of class I–restricted CD8+ T cells to coactivate and polarize DCs may support the induction of Th1-type responses against class I–presented epitopes of intracellular pathogens and contact allergens, and may have therapeutical implications in cancer and chronic infections.

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