scholarly journals Inhibition of calcium signalling in murine splenocytes by polyamines: differential effects on CD4 and CD8 T-cells

1993 ◽  
Vol 291 (2) ◽  
pp. 375-381 ◽  
Author(s):  
T Thomas ◽  
U B Gunnia ◽  
E J Yurkow ◽  
J R Seibold ◽  
T J Thomas
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Cell Subsets ◽  
Free Calcium ◽  
Dependent Manner ◽  
Con A ◽  
Acetoxymethyl Ester ◽  
Murine Splenocytes ◽  
Dose Dependent

Transmembrane Ca2+ influx is recognized as a universal second messenger that transduces T-cell activation signals to cytoplasm and nucleus, thereby stimulating transcription and cell division. To examine the role of endogenous factors that regulate mitogenic Ca2+ signalling of T-cells, we measured the concanavalin (Con) A-induced increase in cytoplasmic free calcium ([Ca2+]i) in spleen cells of BALB/c mice, using flow cytometry with an indicator dye, Indo-1 acetoxymethyl ester (Indo-1/AM). Con A is a polyclonal activator of T-cells. Unstimulated splenocytes had a [Ca2+]i of 100 nM. [Ca2+]i increased with Con A in a dose-dependent manner up to a concentration of 50 micrograms/ml. In the presence of 50 micrograms/ml Con A, [Ca2+]i was 350 nM. Natural polyamines (putrescine, spermidine and spermine) inhibited Con-A-induced Ca2+ influx in a dose-dependent manner. Putrescine was the most effective polyamine in desensitizing the Ca2+ signal, and decreased [Ca2+]i from 350 nM in the absence of putrescine to 250 nM in the presence of 100 microM putrescine. This effect was not mimicked by structurally related homologues or inorganic cations, suggesting a specific structural effect of the polyamine. H.p.l.c. analysis showed that polyamines were internalized during incubation of cells in vitro. In experiments using monoclonal anti-CD4 and anti-CD8 antibodies, we found a differential effect of putrescine on Ca2+ influx in CD4 and CD8 subpopulations of T cells. For CD4+ cells, [Ca2+]i decreased from 625 nM to 420 nM in the presence of 500 microM putrescine, whereas [Ca2+]i was not affected by putrescine in CD8+ cells. These data suggest that natural polyamines have cell-specific effects on mitogen-stimulated Ca(2+)-influx in T-cell subsets.

scholarly journals Spontaneous and glucocorticoid-induced apoptosis in human mature T lymphocytes

Blood ◽  
1995 ◽  
Vol 86 (11) ◽  
pp. 4199-4205 ◽  
Author(s):  
M Brunetti ◽  
N Martelli ◽  
A Colasante ◽  
M Piantelli ◽  
P Musiani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Number ◽  
T Cell Subsets ◽  
Dependent Manner ◽  
Cell Repertoire ◽  
Induced Apoptosis ◽  
And Function ◽  
Dose Dependent

Glucocorticoid (GC)-induced apoptosis is a well-recognized physiologic regulator of murine T-cell number and function. We have analyzed its mechanisms in human mature T cells, which have been thought to be insensitive until recently. Peripheral blood T cells showed sensitivity to GC-induced apoptosis soon after the proliferative response to a mitogenic stimulation, and were also sensitive to spontaneous (ie, growth factor deprivation-dependent) apoptosis. CD8+ T cells were more sensitive to both forms than CD4+ T cells. Acquisition of sensitivity to GC-induced apoptosis was not associated with any change in number or affinity of GC receptors. Both spontaneous and GC-induced apoptosis were increased by the macromolecular synthesis inhibitors, cycloheximide (CHX) and puromycin. A positive correlation between the degree of protein synthesis inhibition and the extent of apoptosis was observed. Interleukin-2 (IL-2) IL-4, and IL-10 protected (IL-2 > IL-10 > IL-4) T cells from both forms of apoptosis in a dose-dependent manner. Our data suggest that spontaneous and GC-induced apoptosis regulate the human mature T-cell repertoire by acting early after the immune response and differentially affecting T-cell subsets.

Interaction of Human Mesenchymal Stem Cells with Alloantigen-Induced T Lymphocyte Activation Favors the Differentiation of CD4+ T Cell Subsets Expressing CD25 and/or CTLA4 Molecules.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2123-2123
Author(s):  
Rita Maccario ◽  
Marina Podestà ◽  
Antonia Moretta ◽  
Angela Cometa ◽  
Patrizia Comoli ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Mesenchymal Stem Cells ◽  
Lymphocyte Activation ◽  
Third Party ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Dose Dependent

Abstract Experimental evidence and preliminary clinical studies have demonstrated that human mesenchymal stem cells (MSCs) display important immune modulatory function of potential relevant interest in the setting of allogeneic hematopoietic stem cell (HSC) transplantation. Effectiveness of MSCs in controlling severe GVHD seems to be related to the immune-regulatory role they play in suppressing alloantigen-specific T-cell activation. Aim of the present study was to extend the analysis of the mechanisms responsible for the immune regulatory effect of interaction between MSCs and alloantigen-specific immune response elicited in vitro in primary and in secondary mixed lymphocyte culture (MLC). At difference with most previously reported studies, we decided to employ non-irradiated MSCs, reasoning that irradiation might impair, beside the proliferative capacity, also the differentiation capability of MSCs and, consequently, alter their interaction pattern with lymphocyte subsets. MSC were added to primary MLC at different doses (MLC-responder-PBMC:MSC ratios = 1:1 and 10:1). Dendritic cell (DC) differentiation, lymphocyte proliferation, alloantigen-specific cytotoxic activity and differentiation of CD4+ T-cell subsets expressing CD25 and/or CTLA4 antigens were assessed in primary and secondary MLC, comparing the effect observed using third-party MSCs with that obtained employing autologous to the MLC-responder (autologous) MSCs. Results demonstrated that human MSCs: (1) strongly inhibit alloantigen-induced DC1 differentiation; (2) down-regulate, in a dose-dependent manner, alloantigen-induced lymphocyte expansion, especially that of CD8+ T cells and of NK lymphocytes; (3) favor the differentiation of CD4+ T cells co-expressing CD25 and/or CTLA4, a phenotype associated with regulatory/suppressive function of immune response; (4) cause a dose-dependent reduction of alloantigen-specific cytotoxic capacity mediated by either cytotoxic T lymphocytes or NK cells; (5) exert more effective suppressive activity on MLC-induced T-cell activation when they are allogeneic rather than autologous with respect to responder cells. In particular, higher percentages of CD4+ and of CD4+CD25+ T cells co-expressing CTLA4+ were detected when third-party, rather than autologous, MSCs were added to MLC. These data suggest that T-cell recognition of alloantigens expressed by MSCs may further facilitate the preferential differentiation of activated CD4+ T cells expressing CTLA4, a glycoprotein, known to deliver an inhibitory signal to T cells and to mediate apoptosis of previously activated T lymphocytes. Several studies previously demonstrated that MSCs exert inhibitory effect on lymphocyte activation through the release of soluble factors. Our data suggest that the preferential differentiation of CD4+CD25+ regulatory T-cell subsets may be favored by other mechanisms of MSC-mediated inhibition of alloantigen-induced effector cell activation and expansion, and, in turn, these CD4+CD25+ cells contribute to propagate and extend suppressor activity. Altogether, our results provide immunological support to the use of MSCs for prevention of immune complications related to both HSC and solid organ transplantation and to the theory that MSCs are “universal” suppressors of immune reactivity.

Immune Effects of Imatinib in Chronic Myelogenous Leukemia In Vitro.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2956-2956
Author(s):  
Dagmar Bund ◽  
Raymund Buhmann ◽  
Hans-Jochem Kolb
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Myelogenous Leukemia ◽  
Dependent Manner ◽  
Activation Markers ◽  
Antigen Presenting ◽  
Dose Dependent

Abstract Imatinib mesylate, a potent and selective inhibitor of the BCR-ABL tyrosine kinase, has been shown to induce durable haematological and major cytogenetic responses in a high percentage of CML patients. However in most patients the disease recurs, when imatinib is discontinued. In contrast, allogeneic stem cell transplantation (ASCT) is considered to be curative by the immune effect of donor T cells against CML progenitor cells. In this context, the role of imatinib is controversial; it may improve the results of ASCT by reducing the tumour load, it may also reduce the effect of donor lymphocyte transfusions (DLT) by impairing the function of T cells and the capacity of myeloid cells to present antigen. Patient derived CML-cells were studied for the stimulation of allogeneic HLA-matched and mismatched T-cells in the presence and absence of imatinib. In a 5 day culture the proliferative response of HLA-mismatched T cells was evaluated in presence of different concentrations of imatinib (0, 1, 2, or 5 micro M) and various responder-to-stimulator ratios. Thereby, proliferation was detected via a CFDA based assays and the activation profile (CD25, CD69) of the T-cells was determined by FACS. Cr51-release assays were performed after a 7 day culture of CML cells with HLA-matched T cells to test cytotoxicity of CD8+ T-cells. In addition, we characterized the antigen-presenting profile (CD14, CD33, HLA-DR, CD40, CD80, CD86, CD54, CD58) of the CML cells over a 5 day culture with and without imatinib. The presence of imatinib inhibited the proliferative capacity of allogeneic T-cells in a dose-dependent manner. Also, the expression of T cell activation markers was reduced in the presence of the different imatinib concentrations. Preincubation of CML cells with imatinib for 48 hours strengthened the effect on proliferation and activation of T cells. Moreover, imatinib impaired the cytotoxic function of T-cell (HLA-matched setting; CR51-release assay) also in a dose-dependent manner. Finally, the antigen-presenting profile of the myeloid leukemia cells was down regulated by increasing concentrations of imatinib. In summary, imatinib may interfere with the T cellular immune response and the antigen presenting profile on the CML cells in vitro. These results may have an impact on new strategies of treatment of CML with immunotherapy.

scholarly journals BTN2A, a New Immune-Checkpoint Targeting Vg9Vd2 T Cell Cytotoxicity

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1044-1044
Author(s):  
Carla E Cano ◽  
Christine Pasero ◽  
Aude De Gassart ◽  
René Hoet ◽  
Emmanuel Scotet ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Ectopic Expression ◽  
Dependent Manner ◽  
Cell Cytotoxicity ◽  
Wild Type ◽  
Primary Tumors ◽  
Dose Dependent ◽  
T Cell Cytotoxicity

Background: Anti-tumoral response of Vg9Vd2 T cells requires sensing of phosphoantigens accumulated in malignant cells through binding of butyrophilin 3A(BTN3A). Moreover, an unknown partner located in human Chr6 was shown to be mandatory to BTN3A-mediated Vg9Vd2 T cell activation in murine models. Here, we identified butyrophilin 2A (BTN2A), which is located to Chr6, as a requirement for BTN3A-mediated Vg9Vd2 T cell cytotoxicity against cancer cells. Methods: CRISPR-Cas9-mediated inactivation of BTN2A1/2A2 isoforms was performed in Daudi, K562 and HEK-293T cells. Vg9Vd2 T cells expanded from healthy PBMCs were co-cultured with wild-type or BTN2AKO cells +/- BrHPP (1 µM), HMBPP (0.1 µM) or zoledronate (45 µM), or anti-BTN2A mAb, and Vg9Vd2 T cell degranulation (%CD106ab+ cells), and intracellular TNFa and IFNg assessed after 4h. Mouse T cell hybridoma 53/4 expressing TCRVg9Vd2-MOP were co-cultured overnight with NIH3T3 murine fibroblasts transfected with BTN3A- and/or BTN2A-encoding plasmids +/-HMBPP(10 µM), or increasing doses of HMBPP or anti-BTN3 20.1 mAb. BTN2A transcript expression in normal vs. tumoral tissue was analyzed using GEPIA tool. Anti-BTN2A mAb staining was performed on human samples of primary AML, cervical and pancreatic carcinoma and assessed by flow cytometry. Results: Degranulation and intracellular IFNg/TNFa (n=6) were abolished in Vg9Vd2 T cells co-cultured with BTN2AKO Daudi, K562 and HEK-293T cells compared to wild-type, in all conditions tested including anti-BTN3 20.1. Murine cells do not express no BTN2A1 or BTN3A orthologs and are unable to activate human Vg9Vd2 T cells. Ectopic expression of BTN2A and BTN3A combination but neither BTN2A or BTN3A alone in murine NIH3T3 cells, allows triggering of IL-2 secretion in mouse 53/4-TCRVg9Vd2-MOP reporter cells in presence of HMBPP or 20.1 mAb in dose-dependent manner. Anti-BTN2A mAb was able to suppress Vg9Vd2 T cell degranulation/cytokine secretion against cancer cell lines and activation of mouse 53/4-TCRVg9Vd2-MOP reporter by BTN2A/BTN3A-expressing NIH3T3 in a dose-dependent manner. BTN2A transcript was significantly up-regulated in pancreatic, ovarian and cervical carcinoma vs. normal tissue. Extracellular BTN2A protein was detected in primary hematological and solid tumors. Conclusion: Here, we show that BTN2A is mandatory for BTN3A-mediated function in human Vg9Vd2 T cells. Moreover, concomitant BTN2A and BTN3A expression empowers murine T cells with activation through Vg9Vd2 TCR, opening new roads for mouse models of Vg9Vd2 T cell anti-tumoral responses. We describe an anti-BTN2A able to suppress Vg9Vd2 T cell function, and we show BTN2A expression in primary tumors. These results are relevant for understanding Vg9Vd2 T cell antitumoral immunity triggered by phosphoantigens and amino-bisphosphonates. Disclosures Olive: ImCheck Therapeutics: Consultancy, Equity Ownership, Patents & Royalties; GlaxoSmithKline: Patents & Royalties.

IFN-Alpha and gm-CSF Can Reverse Immunomodulatory Effects of Imatinib

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2903-2903
Author(s):  
Dagmar Bund ◽  
Raymund Buhmann ◽  
Hans Jochem Kolb
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Dependent Manner ◽  
Immunomodulatory Effects ◽  
Gm Csf ◽  
Ifn Alpha ◽  
Dose Dependent

Abstract Presently, Imatinib (IM) is the first line therapy for chronic myeloid leukaemia (CML), but in most patients CML recurs after discontinuation of IM. In contrast, allogeneic stem cell transplantation (ASCT) is considered to be the only curative treatment for this malignancy curing by the immune effects of donor T-cells against CML progenitor cells. Recent reports have described that IM has inhibitory effects on both the function of T-cells and antigen presenting cells (APCs) like dendritic cells. In the present study we further characterized the immunomodulatory effects of IM on T-cells and APCs and analysed whether IFN-alpha (interferon alpha, IFN-a) alone or in combination with GM-CSF (granulocyte-macrophage colony-stimulating factor) can influence the negative IM effects in vitro. Patient derived CML cells were examined to stimulate allogeneic HLA-mismatched T-cells without and with Imatinib (1, 2 or 5 micro M). The activation profile (CD25) and the expression of the TCR-alpha (T-cell receptor) on the T-cells was determined by FACS after 5 days in presence of IM as well as the proliferative T-cell response which was evaluated using CFSE (Carboxy Fluoroscein Succinimidyl Ester). In [51Cr]-release assays the cytotoxicity of CD8+ T-cells was assessed. The cytokine profile of the culture supernatants was detected by CBA (Cytokine bead array, Beckton Dickinson, USA). We also characterized the antigen profile (HLA-DR, CD40, CD54, CD58, CD80 and CD86) of the CML cells as APCs over a 5 day culture with and without IM. The rescue of the CML cells was initiated by IFN-a or IFN-a/GM-CSF after 3 days incubation with IM. On day 6 the APC profile of the CML cells was obtained and cells were used as stimulators in terms of T-cell proliferation which was determined by CFSE. We could show that the proliferation of allogeneic T-cell was inhibited in the presence of IM in a dose-dependent manner. In addition, the T-cell activation marker CD25 and the TCR-alpha expression were significantly downregulated by different concentrations of IM. Moreover, IM impaired the cytotoxic function of allogeneic T-cells in a dose-dependent manner. Interestingly, after stimulation with CML-cells cytotoxic T-cell activity could only be induced in those cases that did not secrete IL-6. Down-regulation of the APC profile on CML-cells (adhesion/costimulatory molecules) by increasing concentrations of IM could be in part reversed by the addition of IFN-a and completely restored by the combination of IFN-a and GM-CSF. Although, the proportion of proliferating T-cells could not be increased further by the combination of IFN-a ± GM-CSF, the number of T-cells was increased in the presence of IFN-a + GM-CSF. In conclusion, the down-modulating effects of IM could be almost completely reversed by the addition of IFN-a and GM-CSF. It remains to be seen whether these findings can be successfully applied to the treatment of CML-patients.

scholarly journals 795 APVO603: a dual 4-1BB and OX40 bispecific approach utilizing ADAPTIRTM technology designed to deliver a conditional T cell/NK response against solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A830-A830
Author(s):  
Michelle Nelson ◽  
Ashly Lucas ◽  
Rebecca Gottschalk ◽  
Catherine McMahan ◽  
Jane Gross ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Bispecific Antibody ◽  
Expression Profiles ◽  
T Cell Subsets ◽  
Dependent Manner ◽  
Dose Dependent

BackgroundAPVO603 is a dual targeting bispecific antibody for 4-1BB (CD137) and OX40 (CD134), engineered with Aptevo's ADAPTIRTM technology. We have previously shown that the distinct characteristics of APVO603 may enable conditional agonism of 4-1BB and OX40 only when cross-linked through engagement of the other receptor via cis and/or trans cellular interactions. Thus, APVO603 is designed with the potential to overcome both the on-target toxicity and limited efficacy observed with 4-1BB and OX40 monoclonal antibody treatment in the clinic.MethodsGenevestigator Software was used to analyze curated transcriptomic data for the expression profiles of OX40 and 4-1BB across select human heme and solid cancer patient sample data sets, as well as, non diseased tissue. Primary inducible Treg (iTreg) cells were sub-optimally stimulated with an anti-CD3/CD28 antibody and cell proliferation was assessed using CFSE-labelled. Cytokines were measured using intracellular flow-based methods. For in vitro tumor lysis studies, activated T cells were co-cultured with Nuclight-labelled tumor cells expressing a tumor-associated antigen (TAA) and activated with TAA x CD3 bispecific protein. Live tumor cells were continually assessed using the Incucyte Live-Cell Analysis System and Cell-By-Cell Software Module.ResultsOX40 and 4-1BB displayed distinct tumor expression profiles, however, several tumor indications were identified with high co-expression and may aid in identifying indications for the clinical development of APVO603. In vitro, APVO603 favored activation of effector T cell subsets and had minimal impact in augmenting iTreg cells proliferation, cytokine production or expression of effector-related molecules, despite the fact that a portion of the iTreg cells expressed OX40 and 4-1BB. The mechanistic activity of APVO603 resulted in dose-dependent control of in vitro tumor growth when paired with a T-cell activating TAA x CD3 bispecific under standard conditions or those leading to T cell exhaustion. In preclinical assays using PBMCs sub-optimally stimulated with TAA x CD3, APVO603 enhanced TAA-expressing tumor cell lysis when compared to TAA x CD3 alone.ConclusionsAPVO603 is a dual-agonistic bispecific antibody that augments the effector function of activated CD4+ and CD8+ T cells and NK cells, but not iTreg cells, in a dose-dependent manner and reduces growth of tumors in vitro and in vivo. Further, mechanistic evaluation supports the ability of APVO603 to pair with T-cell modulating IO approaches to support a more fit T cell response and favorable TME. This preclinical data supports further development of APVO603, a promising immuno-oncology therapeutic with potential for benefit in hematologic and solid tumors.

scholarly journals CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

2021 ◽  
Vol 9 (4) ◽  
pp. e002051
Author(s):  
Ryan Michael Reyes ◽  
Yilun Deng ◽  
Deyi Zhang ◽  
Niannian Ji ◽  
Neelam Mukherjee ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Combination Treatment ◽  
Treatment Efficacy ◽  
Interleukin 2 ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Γδ T Cell

BackgroundAnti-programmed death-ligand 1 (αPD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in <30% of patients. Interleukin (IL)-2/αIL-2 complexes (IL-2c) that preferentially target IL-2 receptor β (CD122) augment CD8+ antitumor T cells known to improve αPD-L1 efficacy. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1.MethodsWe studied mechanisms of IL-2c and αPD-L1 efficacy using PD-L1+ mouse BC cell lines MB49 and MBT-2 in orthotopic (bladder) and metastatic (lung) sites.ResultsIL-2c reduced orthotopic tumor burden and extended survival in MB49 and MBT-2 BC models, similar to αPD-L1. Using antibody-mediated cell depletions and genetically T cell-deficient mice, we unexpectedly found that CD8+ T cells were not necessary for IL-2c efficacy against tumors in bladder, whereas γδ T cells, not reported to contribute to αPD-L1 efficacy, were indispensable for IL-2c efficacy there. αPD-L1 responsiveness in bladder required conventional T cells as expected, but not γδ T cells, altogether defining distinct mechanisms for IL-2c and αPD-L1 efficacy. γδ T cells did not improve IL-2c treatment of subcutaneously challenged BC or orthotopic (peritoneal) ovarian cancer, consistent with tissue-specific and/or tumor-specific γδ T cell contributions to IL-2c efficacy. IL-2c significantly altered bladder intratumoral γδ T cell content, activation status, and specific γδ T cell subsets with antitumor or protumor effector functions. Neither IL-2c nor αPD-L1 alone treated lung metastatic MB49 or MBT-2 BC, but their combination improved survival in both models. Combination treatment efficacy in lungs required CD8+ T cells but not γδ T cells.ConclusionsMechanistic insights into differential IL-2c and αPD-L1 treatment and tissue-dependent effects could help develop rational combination treatment strategies to improve treatment efficacy in distinct cancers. These studies also provide insights into γδ T cell contributions to immunotherapy in bladder and engagement of adaptive immunity by IL-2c plus αPD-L1 to treat refractory lung metastases.

scholarly journals Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Qiuli Liu ◽  
Xiaoyong Chen ◽  
Chang Liu ◽  
Lijie Pan ◽  
Xinmei Kang ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Liver Injury ◽  
T Cell Activation ◽  
Gene Set Enrichment Analysis ◽  
Human Umbilical Cord ◽  
Con A ◽  
Immune Mediated

AbstractLiver diseases with different pathogenesis share common pathways of immune-mediated injury. Chitinase-3-like protein 1 (CHI3L1) was induced in both acute and chronic liver injuries, and recent studies reported that it possesses an immunosuppressive ability. CHI3L1 was also expressed in mesenchymal stem cells (MSCs), thus we investigates the role of CHI3L1 in MSC-based therapy for immune-mediated liver injury here. We found that CHI3L1 was highly expressed in human umbilical cord MSCs (hUC-MSCs). Downregulating CHI3L1 mitigated the ability of hUC-MSCs to inhibit T cell activation, proliferation and inflammatory cytokine secretion in vitro. Using Concanavalin A (Con A)-induced liver injury mouse model, we found that silencing CHI3L1 significantly abrogated the hUC-MSCs-mediated alleviation of liver injury, accompanying by weakened suppressive effects on infiltration and activation of hepatic T cells, and secretion of pro-inflammatory cytokines. In addition, recombinant CHI3L1 (rCHI3L1) administration inhibited the proliferation and function of activated T cells, and alleviated the Con A-induced liver injury in mice. Mechanistically, gene set enrichment analysis showed that JAK/STAT signalling pathway was one of the most significantly enriched gene pathways in T cells co-cultured with hUC-MSCs with CHI3L1 knockdown, and further study revealed that CHI3L1 secreted by hUC-MSCs inhibited the STAT1/3 signalling in T cells by upregulating peroxisome proliferator-activated receptor δ (PPARδ). Collectively, our data showed that CHI3L1 was a novel MSC-secreted immunosuppressive factor and provided new insights into therapeutic treatment of immune-mediated liver injury.

scholarly journals Functional analysis of T cells expressing Ia antigens. I. Demonstration of helper T-cell heterogeneity.

1979 ◽  
Vol 150 (6) ◽  
pp. 1293-1309 ◽  
Author(s):  
J E Swierkosz ◽  
P Marrack ◽  
J W Kappler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Keyhole Limpet Hemocyanin ◽  
T Cell Subsets ◽  
Cytotoxic Lymphocytes ◽  
Lymphocyte Function ◽  
Con A ◽  
Helper T Cell ◽  
Effector Cells ◽  
Ia Antigens

We have examined the expression of I-region antigens on functional subpopulations of murine T cells. A.TH anti-A.TL (anti-Ik, Sk, Gk) alloantiserum was raised by immunization of recipients with concanavalin A (Con A) stimulated thymic and peripheral T-cell blasts. In contrast to similar antisera made by conventional methods, the anti-Ia blast serum was highly cytotoxic for purified T lymphocytes. Moreover, it reacted in a specific fashion with T cells having particular functions. Treatment of keyhole limpet hemocyanin (KLH)-primed B10.A (H-2 alpha) T cells with this antiserum plus complement resulted in the elimination of helper activity for B-cell responses to trinitrophenyl-KLH. Inhibition was shown to be a result of the selective killing of one type of helper T cell whose activity could be replaced by a factor(s) found in the supernate of Con A-activated spleen cells. A second type of helper cell required for responses to protein-bound antigens appeared to be Ia-. By absorption and analysis on H-2 recombinants, at least two specificities were detectable on helper T cells; one mapping in the I-A subregion and a second in a region(s) to the right of I-J. In addition, the helper T cell(s) involved in the generation of alloreactive cytotoxic lymphocytes was shown to be Ia+, whereas cytotoxic effector cells and their precursors were Ia- with this antiserum. These results provide strong evidence for the selective expression of I-region determinants on T-cell subsets and suggest that T-cell-associated Ia antigens may play an important role in T-lymphocyte function.

scholarly journals Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea

2017 ◽  
Vol 50 (4) ◽  
pp. 1700833 ◽  
Author(s):  
Carolina Cubillos-Zapata ◽  
Jose Avendaño-Ortiz ◽  
Enrique Hernandez-Jimenez ◽  
Victor Toledano ◽  
Jose Casas-Martin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Intermittent Hypoxia ◽  
Cell Activation ◽  
Cell Function ◽  
Sleep Apnoea ◽  
Orphan Receptor ◽  
Dependent Manner ◽  
Obstructive Sleep

Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients.

Sign in / Sign up

Export Citation Format

Share Document