IFN-γ: The T cell’s license to kill stem cells in the inflamed intestine

2019 ◽  
Vol 4 (42) ◽  
pp. eaaz6821
Author(s):  
Kai Kretzschmar ◽  
Hans Clevers
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Cell Death ◽  
Stem Cell ◽  
Intestinal Injury ◽  
Intestinal Stem Cell ◽  
Related Research ◽  
Link Type ◽  
Research Article ◽  
Ifn Γ

IFN-γ produced by T cells directly induces intestinal stem cell death upon inflammation-induced intestinal injury (see the related Research Article byTakashimaet al.).

P2X7R: The Achilles heel of follicular helper memory T cells

2020 ◽  
Vol 5 (45) ◽  
pp. eaba8097
Author(s):  
Jeffrey C. Nolz
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Memory T Cells ◽  
Related Research ◽  
Link Type ◽  
Follicular Helper ◽  
Research Article

Protecting TFH memory CD4+ T cells from NAD-induced cell death reveals both their longevity and plasticity (see related Research Article by Künzli et al.).

Tregs in fibrosis: To know your enemy, you must become your enemy

2019 ◽  
Vol 4 (39) ◽  
pp. eaay1160 ◽  
Author(s):  
Suzanne M. Bal ◽  
Ralph Stadhouders
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cytokine Production ◽  
T Helper ◽  
Related Research ◽  
T Helper 2 ◽  
Link Type ◽  
Research Article

T helper 2–skewed regulatory T cells in the skin use GATA3 to suppress local profibrotic type 2 cytokine production. See the related Research Article by Kalekar et al.

Treatment with Tyrosine Kinase Inhibitors May Impair the Potential Curative Effect of Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 857-857
Author(s):  
Inge Jedema ◽  
Linda van Dreunen ◽  
Roelof Willemze ◽  
J.H. Frederik Falkenburg
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Cell Death ◽  
Stem Cell ◽  
Kinase Inhibitors ◽  
Leukemic Cells ◽  
High Avidity ◽  
Curative Effect ◽  
Donor T Cells ◽  
Tki Treatment

Abstract Abstract 857 Tyrosine kinase inhibitors (TKI) like imatinib and dasatinib are the current treatment of choice for patients with chronic myeloid leukemia (CML). Although most patients enter a complete remission during treatment, cure of the disease is usually not achieved since recurrence of the disease is seen in the majority of patients upon discontinuation of the treatment, indicating that the leukemic stem cell is not efficiently targeted. Furthermore, in accelerated phase and blast crisis of CML TKI treatment only results in temporary control of the disease. In these situations allogeneic stem cell transplantation (allo-SCT) and application of donor T cells may be the only curative treatment. Besides the direct anti-leukemic effect of allo-SCT, alloreactive T cells recognizing CML (progenitor) cells, and the formation of immunological memory may lead to effective lifelong immune surveillance. Therefore, we investigated whether the leukemic cells persisting during TKI treatment are susceptible targets for the anti-leukemic effect mediated by donor T cells after allo-SCT and whether continuous TKI treatment may have an additive effect during the immunological intervention. To investigate the anti-leukemic effect of the two strategies, CD34+ positive CML cells were isolated from bone marrow, and labeled with the fluorescent dyes CFSE or PKH to allow monitoring of single cell proliferation. CML cells were exposed to imatinib (1-100μM) or dasatinib (0.01-50nM), and/or to CD8+ alloreactive cytotoxic T lymphocyte (CTL) clones in the presence of proliferation-inducing cytokines. The number, phenotype, and proliferative status of the CML cells persisting after single and combined interventions were measured by quantitative flowcytometric analysis. In the absence of therapeutic interventions the majority of CD34+ CML cells entered proliferation. However, a small population of CD34+ CML stem cells residing in the non-dividing peak could be identified despite the addition of cytokines. Addition of imatinib or dasatinib resulted in efficient dose-dependent induction of cell death of the leukemic cells (99% lysis by 25μM imatinib or 10nM dasatinib). However, the population of quiescent CD34+ CML stem cells was not affected. Moreover, the number of cells present in the non-dividing population increased 2-fold compared to the non-treated controls at the highest TKI concentrations, indicating additional growth arrest of a population of proliferating CML precursor cells. We next tested the capacity of different HLA-A2-restricted CD8+ CTL clones to kill non-treated or imatinib or dasatinib treated CML cells. Whereas the proliferating CD34+ CML precursors were efficiently lysed, the population of quiescent stem cells was capable of withstanding CTL exposure. Detailed phenotypic analysis revealed significant downregulation of HLA-A2 and the adhesion molecules CD49d and CD58 on these quiescent cells, probably resulting in the impaired ability of these target cells to form a high avidity interaction with the T cells. The increased population of non-dividing cells as a result of the TKI pretreatment showed similar resistance to T cell induced cell death, indicating that TKI treatment may even diminish the anti-leukemic effect of allo-SCT. In the absence of therapeutic control, as mimicked by the removal of T cells and TKI from the cultures, outgrowth of the leukemic cells re-occurred, illustrating their capacity to give rise to a relapse of the disease. Next, we analyzed the effect of TKI treatment on T cell survival and functionality. Whereas resting primary T cells were insensitive to TKI treatment, T cells activated by either polyclonal stimulation with anti-CD3/CD28 beads or stimulation with allogeneic stimulator cells died after TKI exposure at similar concentrations as the leukemic cells. In conclusion, TKI treatment results in selection of a population of quiescent leukemic stem cells showing cross-resistance to CTL-induced cell death, most likely due to their inability to form a high avidity interaction. Moreover, T cells actively participating in the anti-leukemic immune response after allo-SCT are suppressed by TKI. These data indicate that continuous TKI treatment may potentially hamper the curative effect of allo-SCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Lighting a fire on the reef

2020 ◽  
Vol 5 (54) ◽  
pp. eabf0905
Author(s):  
Zhibin Zhang ◽  
Judy Lieberman
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Caspase 3 ◽  
Bacterial Pathogen ◽  
Related Research ◽  
Link Type ◽  
Research Article

Coral gasdermin E is cleaved by activated caspase-3 to induce pyroptosis, a form of inflammatory programmed cell death, in response to a bacterial pathogen (see the related Research Article by Jiang et al.).

Myeloid cells in the central nervous system: So similar, yet so different

2019 ◽  
Vol 4 (32) ◽  
pp. eaaw2841 ◽  
Author(s):  
Francisco J. Quintana
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Myeloid Cells ◽  
Related Research ◽  
Link Type ◽  
Research Article ◽  
The Central Nervous System

Dissection of the heterogeneity of CNS myeloid cells reveals functionally distinct subsets that govern encephalitogenic T cells. See related Research Article by Jordão et al.

scholarly journals Suppressing Pyroptosis Augments Post-Transplant Survival of Stem Cells and Cardiac Function Following Ischemic Injury

2021 ◽  
Vol 22 (15) ◽  
pp. 7946
Author(s):  
Chang Youn Lee ◽  
Seahyoung Lee ◽  
Seongtae Jeong ◽  
Jiyun Lee ◽  
Hyang-Hee Seo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Stem Cell ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion ◽  
Cardiac Cells ◽  
Transplant Survival ◽  
Post Transplant ◽  
Heart Functions ◽  
Cell Death Mechanisms

The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1b production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.

scholarly journals Mitochondria regulate intestinal stem cell proliferation and epithelial homeostasis through FOXO

2020 ◽  
Vol 31 (14) ◽  
pp. 1538-1549
Author(s):  
Fan Zhang ◽  
Mehdi Pirooznia ◽  
Hong Xu
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Stem Cell ◽  
Electron Transport Chain ◽  
Intestinal Stem Cell ◽  
Stem Cell Proliferation ◽  
Epithelial Homeostasis ◽  
Chain Complexes ◽  
Transport Chain

Deficiencies in electron transport chain complexes increase the activity of FOXO transcription factor in Drosophila midgut stem cells, which impairs stem cell proliferation and enterocyte specification.

scholarly journals The Immunomodulatory Effect of Triptolide on Mesenchymal Stem Cells in Vitro

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5011-5011
Author(s):  
Haiping He ◽  
Atsuko Takahashi ◽  
Yuki Yamamoto ◽  
Akiko Hori ◽  
Yuta Miharu ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Complete Medium ◽  
Surface Markers ◽  
Rt Pcr ◽  
Tnf Α ◽  
Ifn Γ

Background: Mesenchymal stromal cells (MSC) are known to have the immunosuppressive ability and have been applied in clinic to treat acute graft-versus-host disease (GVHD), as one of severe complications after hematopoietic stem cells transplantation (HSCT) in Japan. However, MSC are activated to suppress the immune system only upon the stimulation of inflammatory cytokines and the clinical results of MSC therapies for acute GVHD are varied. It is ideal that MSC are primed to be activated and ready to suppress the immunity (=priming) before administration in vivo. Triptolide (TPL) is a diterpene triepoxide purified from a Chinese herb - Tripterygium Wilfordii Hook F (TWHF). It has been shown to possess anti-inflammatory and immunosuppressive properties in vitro. In this study, we aim to use TPL as the activator for umbilical cord-derived MSC (UC-MSC) to entry stronger immunosuppressive status. Methods: The proliferation of UC-MSC with TPL at the indicated concentrations for different time of 24, 48, 72, and 96 hours. Cell counting kit-8(CCK-8) was added in the culture medium to detect cell toxicity and the absorbance was measured using microplate reader. Flow cytometry was used to identify the MSC surface markers expression. TPL-primed UC-MSC were once replaced with fresh medium and co-culture with mixed lymphocyte reaction (MLR) consisted with mononuclear cells (MNCs) stained with CFSE and irradiated allogenic dendritic cell line (PMDC05) in RPMI 1640 medium supplemented with 10 % FBS (complete medium). IDO-1, SOD1, and TGF-β gene expression in TPL-primed UC-MSC and UC-MSC induced by 10 ng/ml IFN-γ and/or 15 ng/ml TNF-α were evaluated by RT-PCR. PDL1 and PDL2 expression in TPL-primed UC-MSC and UC-MSC in response to IFN-γ and/or TNF-α were checked by Flowjo. Results: Exposure of TPL for UC-MSC for 72hour at the concentration above 0.1 μM resulted in the cell damage significantly. Therefore, we added TPL in UC-MSC at 0.01μM of TPL for up to 48 hours, then washed thourouphly for the following culture for experiments. To evaluate the influence of TPL on the surface markers of UC-MSC, we cultured UC-MSC for 4 hours in complete medium following culture with 0.01μM of TPL for 20 hours (TPL-primed UC-MSC). TPL-primed UC-MSC revealed positive for CD105, CD73, and CD90, negative for CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR surface molecules as same as the non-primed UC-MSC. In MLR suppression by UC-MSC, the TPL-primed UC-MSC activity revealed stronger anti-proliferative effect on the CD4+ and CD8+ T cells activated by allogeneic DC than those of non-primed UC-MSC in MLR. Furthermore, the TPL-primed UC-MSC promoted the expression of IDO-1, SOD1 and TGF-β in response to IFN-γ+/-TNF-α by RT-PCR and enhanced the expression of PD-L1 by FACS analysis. Discussion:In this study, we found the TPL-primed UC-MSC showed stronger antiproliferative potency on CD4+ and CD8+ T cells compared with non-primed UC-MSC. TPL-primed UC-MSC promoted the expression of IDO-1, SOD1 and TGF-β stimulated by IFN-γ+/-TNF-α, although TPL alone did not induce these factors. Furthermore, we found that the PD1 ligand (PD-L1) was induced in TPL-primed UC-MSC, likely IFN-γ enhanced the PD-L1 expression, evaluated by flowcytometry. These results suggested that TPL-primed UC-MSC seemed more sensitive to be activated as the immunosuppressant. Here, we firstly report the new function of TPL to induce the upregulation of immunosuppressive effect, although the mechanisms of TPL inhibition to MSC need to be explore. Conclusively, TPL-primed UC-MSC might be applied for the immunosuppressive inducer of MSC. Figure Disclosures He: SASAGAWA Medical Scholarship: Research Funding; IMSUT Joint Research Project: Research Funding. Nagamura:AMED: Research Funding. Tojo:AMED: Research Funding; Torii Pharmaceutical: Research Funding. Nagamura-Inoue:AMED: Research Funding.

scholarly journals CD34+ Hematopoietic Stem Cells Exert Accessory Function in Lipopolysaccharide-induced  T Cell Stimulation and CD80 Expression on Monocytes

1999 ◽  
Vol 189 (4) ◽  
pp. 693-700 ◽  
Author(s):  
Taila Mattern ◽  
Gundolf Girroleit ◽  
Hans-Dieter Flad ◽  
Ernst T. Rietschel ◽  
Artur J. Ulmer
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Stimulation ◽  
Hematopoietic Stem ◽  
Accessory Function ◽  
T Cell Stimulation ◽  
Blood Stem Cells

CD34+ hematopoietic stem cells, which circulate in peripheral blood with very low frequency, exert essential accessory function during lipopolysaccharide (LPS)-induced human T lymphocyte activation, resulting in interferon γ production and proliferation. In contrast, stimulation of T cells by “conventional” recall antigens is not controlled by blood stem cells. These conclusions are based on the observation that depletion of CD34+ blood stem cells results in a loss of LPS-induced T cell stimulation as well as reduced expression of CD80 antigen on monocytes. The addition of CD34-enriched blood stem cells resulted in a recovery of reactivity of T cells and monocytes to LPS. Blood stem cells could be replaced by the hematopoietic stem cell line KG-1a. These findings may be of relevance for high risk patients treated with stem cells or stem cell recruiting compounds and for patients suffering from endotoxin-mediated diseases.

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