scholarly journals Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Marius Piepke ◽  
Bettina H. Clausen ◽  
Peter Ludewig ◽  
Jonas H. Vienhues ◽  
Tanja Bedke ◽  
...  
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
T Cell ◽  
Regulatory T Cells ◽  
Mouse Models ◽  
Γδ T Cells ◽  
Transgenic Mouse Models ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
Deficient Mice

Abstract Background Lymphocytes have dichotomous functions in ischemic stroke. Regulatory T cells are protective, while IL-17A from innate lymphocytes promotes the infarct growth. With recent advances of T cell-subtype specific transgenic mouse models it now has become possible to study the complex interplay of T cell subpopulations in ischemic stroke. Methods In a murine model of experimental stroke we analyzed the effects of IL-10 on the functional outcome for up to 14 days post-ischemia and defined the source of IL-10 in ischemic brains based on immunohistochemistry, flow cytometry, and bone-marrow chimeric mice. We used neutralizing IL-17A antibodies, intrathecal IL-10 injections, and transgenic mouse models which harbor a deletion of the IL-10R on distinct T cell subpopulations to further explore the interplay between IL-10 and IL-17A pathways in the ischemic brain. Results We demonstrate that IL-10 deficient mice exhibit significantly increased infarct sizes on days 3 and 7 and enlarged brain atrophy and impaired neurological outcome on day 14 following tMCAO. In ischemic brains IL-10 producing immune cells included regulatory T cells, macrophages, and microglia. Neutralization of IL-17A following stroke reversed the worse outcome in IL-10 deficient mice and intracerebral treatment with recombinant IL-10 revealed that IL-10 controlled IL-17A positive lymphocytes in ischemic brains. Importantly, IL-10 acted differentially on αβ and γδ T cells. IL-17A producing CD4+ αβ T cells were directly controlled via their IL-10-receptor (IL-10R), whereas IL-10 by itself had no direct effect on the IL-17A production in γδ T cells. The control of the IL-17A production in γδ T cells depended on an intact IL10R signaling in regulatory T cells (Tregs). Conclusions Taken together, our data indicate a key function of IL-10 in restricting the detrimental IL-17A-signaling in stroke and further supports that IL-17A is a therapeutic opportunity for stroke treatment.

scholarly journals Interleukin-10 Improves Stroke Outcome by Controlling the Detrimental Interleukin-17A Response

2021 ◽  
Author(s):  
Marius Piepke ◽  
Bettina H. Clausen ◽  
Peter Ludewig ◽  
Jonas H. Vienhues ◽  
Tanja Bedke ◽  
...  
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
T Cell ◽  
Regulatory T Cells ◽  
Mouse Models ◽  
Γδ T Cells ◽  
Transgenic Mouse Models ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
Deficient Mice

Abstract Background: Lymphocytes have dichotomous functions in ischemic stroke. Regulatory T cells are protective, while IL-17A from innate lymphocytes promotes the infarcts growth. With recent advances of T cell-subtype specific transgenic mouse models it now has become possible to study the complex interplay of T cell subpopulations in ischemic stroke.Methods: In a murine model of experimental stroke we analyzed the effects of IL-10 on the functional outcome for up to 14 days post-ischemia and defined the source of IL-10 in ischemic brains based on immunohistochemistry, flow cytometry, and bone marrow chimeric mice. We used neutralizing IL-17A antibodies, intrathecal IL-10 injections, and transgenic mouse models which harbor a deletion of the IL-10R on distinct T cell subpopulations to further explore the interplay between IL-10 and IL-17A pathways in the ischemic brain. Results: We demonstrate that IL-10 deficient mice exhibit significantly increased infarct sizes on days three and seven and enlarged brain atrophy and impaired neurological outcome on day fourteen following tMCAO. In ischemic brains IL-10 producing immune cells included regulatory T cells, macrophages, and microglia. Neutralization of IL-17A following stroke reversed the worse outcome in IL-10 deficient mice and intracerebral treatment with recombinant IL-10 revealed that IL-10 controlled IL-17A positive lymphocytes in ischemic brains. Importantly, IL-10 acted differentially on αβ and γδ T cells. IL-17A producing CD4+ αβ T cells were directly controlled via their IL-10-receptor (IL-10R), whereas IL-10 by itself had no direct effect on the IL-17A production in γδ T cells. The control of the IL-17A production in γδ T cells depended on an intact IL10R signaling in regulatory T cells (Tregs). Conclusions: Taken together, our data indicate a key function of IL-10 in restricting the detrimental IL-17A-signaling in stroke and further supports that IL-17A is a therapeutic opportunity for stroke treatment.

scholarly journals Human papillomavirus oncoproteins induce a reorganization of epithelial-associated γδ T cells promoting tumor formation

2017 ◽  
Vol 114 (43) ◽  
pp. E9056-E9065 ◽  
Author(s):  
Dorien Van hede ◽  
Barbara Polese ◽  
Chantal Humblet ◽  
Anneke Wilharm ◽  
Virginie Renoux ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
Γδ T Cells ◽  
Tumor Formation ◽  
T Cell Subsets ◽  
Γδ T Cell ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
The Impact

It has been shown that γδ T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of γδ T cells in human papillomavirus (HPV)-associated uterine cervical SCC, the third-leading cause of death by cancer in women, is unknown. Here, we investigated the impact of γδ T cells in a transgenic mouse model of carcinogenesis induced by HPV16 oncoproteins. Surprisingly, γδ T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16 oncoproteins induced a decrease in epidermal Skint1 expression and the associated antitumor Vγ5+ γδ T cells, which were replaced by γδ T-cell subsets (mainly Vγ6+ γδlowCCR2+CCR6−) actively producing IL-17A. Consistent with a proangiogenic role, γδ T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical biopsies, IL-17A+ γδ T cells could only be observed at the cancer stage (SCC), where HPV oncoproteins are highly expressed, supporting the clinical relevance of our observations in mice. Overall, our results suggest that HPV16 oncoproteins induce a reorganization of the local epithelial-associated γδ T-cell subpopulations, thereby promoting angiogenesis and cancer development.

scholarly journals Lack of gamma delta T cells ameliorates inflammatory response after acute intestinal ischemia reperfusion in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dominik Funken ◽  
Yi Yu ◽  
Xiaoyan Feng ◽  
Tawan Imvised ◽  
Faikah Gueler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokine ◽  
Ischemia Reperfusion ◽  
Γδ T Cells ◽  
Organ Injury ◽  
Distant Organ ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

AbstractT-cells have been demonstrated to modulate ischemia–reperfusion injury (IRI) in the kidney, lung, liver, and intestine. Whereas most T-cell subpopulations contribute primarily to the antigen-specific effector and memory phases of immunity, γδ-T-cells combine adaptive features with rapid, innate-like responses that can place them in the initiation phase of immune reactions. Therefore, we aimed to clarify the role of γδ-T-cells in intestinal IRI. Adult wild-type (WT) and γδ-T-cell-deficient mice were subjected to acute intestinal IRI. Gene expression of pro-inflammatory cytokines and influx of leukocyte subpopulations in the gut were assessed by qPCR and flow cytometry. Serum transaminases were measured as an indicator of distant organ IRI. Intestinal IRI led to increased influx of neutrophils, pro-inflammatory cytokine expression and LDH/ALT/AST elevation. Selective deficiency of γδ-T-cells significantly decreased pro-inflammatory cytokine levels and neutrophil infiltration in the gut following IRI compared to controls. Furthermore, γδ-T-cell deficiency resulted in decreased LDH and transaminases levels in sera, indicating amelioration of distant organ injury. Increasing evidence demonstrates a key role of T-cell subpopulations in IRI. We demonstrate that γδ-T-cell deficiency ameliorated pro-inflammatory cytokine production, neutrophil recruitment and distant organ injury. Thus, γδ-T-cells may be considered as mediators contributing to the inflammatory response in the acute phase of intestinal IRI.

scholarly journals Regulatory T Cells in Melanoma Revisited by a Computational Clustering of FOXP3+ T Cell Subpopulations

2016 ◽  
Vol 196 (6) ◽  
pp. 2885-2892 ◽  
Author(s):  
Hiroko Fujii ◽  
Julie Josse ◽  
Miki Tanioka ◽  
Yoshiki Miyachi ◽  
François Husson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Bone Marrow T Cell Subpopulations in Patients with Newly Diagnosed B-Cell Precursor Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4278-4278
Author(s):  
Peter Brinkrolf ◽  
Silke Landmeier ◽  
Bianca Altvater ◽  
Sibylle Pscherer ◽  
Annegret Rosemann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
Risk Groups ◽  
T Cell Subsets ◽  
Cell Precursor ◽  
Medium Risk ◽  
Pediatric All ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Abstract Besides its role in hemato- and lymphopoiesis, bone marrow (BM) has emerged as a secondary lymphoid organ with important roles in both T cell priming and memory responses. Due to these properties, non-malignant T cells persisting within the BM of patients with acute leukemias may be involved in the immune response to leukemia and the control of minimal residual disease. Here, we investigated the phenotypic signature of residual T cells present at diagnosis in 25 pediatric patients (age 2–16 years) with B cell precursor ALL. Patients with high risk disease including Philadelphia chromosome-positive or MLL-rearranged leukemias were excluded from this analysis. Mononuclear cells were isolated from freshly aspirated BM by density gradient centrifugation and analyzed by six-color-flow cytometry using monoclonal antibodies directed towards various T-cell associated surface and intracellular markers, including CD3/CD56/TCRαβ/TCRγδ/CD86/HLA-DR (Panel 1); CD3/CD4/CD8/CCR7/CD45RA/ CD45RO (Panel 2); CD4/FoxP3/CD25/CD45RA/CD45RO/CCR7 (Panel 3). For each sample, ≥15,000 CD3+ cells (Panel 1, 2) or ≥8,000 CD4+ cells (Panel 3) were analyzed with FACS Canto and Diva Software. The Student’s t test was used to determine statistical significances between individual subgroups, and correlations were performed using the Pearson test. Consistent with published data on BM T cell subsets in healthy donors, the CD4+/CD8+ T cell ratio was 1.32±0.41. The predominant subset among CD8+ T cells (55.2±17.6%) had a naïve T cell phenotype (CD45RA+CCR7+), while 20.7±11.5% were effector memory T cells (TEM; CD45RA-CCR7-), and 7.1±6.2% were central memory T cells (TCM; CD45RA-CCR7+). No differences were found between TEL/AML1 positive or negative leukemias, or between patients stratified into standard (SR) vs. medium risk (MR) groups according to the criteria of the ALL-BFM 2000 study group. T cells bearing γδ T cell receptors have been attributed important roles in the primary immune defense against microbes and in immune control of cancer. We found that 6.9±3.0% (1.8 to 11.8%) of BM T cells were γδTCR+ (Vγ9Vδ2). A statistically significant (p <0.02) difference in the percentage of γδ T cells was found in patients stratified within risk groups MR and SR, respectively (7.0 vs. 4.5%). BM was further found to be a significant reservoir for regulatory T cells (Tregs). The presence of Tregs in the tumor microenvironment has been correlated with an unfavorable prognosis in many types of cancer, indicating a role in tumor immune escape. We found a proportion of 3.6±1.6% FoxP3+CD4+CD25high Tregs among BM CD4+ T cells from all ALL patients. Again, no significant differences were found according to TEL/AML1 status or risk stratification. Recent attention was drawn on the existence of both naïve and memory Treg subpopulations, differing by their expression of CD45RA and CCR7, and conflicting results were reported regarding the relative frequency of either subpopulation. We found a slight predominance of TEM Tregs (47.4±11.4%) above naïve (36.0±10.1%) and TCM Tregs (9.8±4.4%). In summary, while γδ T cells were found at significantly distinct numbers between patients stratified into standard and medium risk groups, no major phenotypic differences were found in residual BM αβ T cell subsets between individual subgroups in non-high-risk pediatric ALL. Future experiments will establish the functional role of the T cell subpopulations in immune control or escape in pediatric ALL.

The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations

Blood ◽  
2014 ◽  
Vol 123 (17) ◽  
pp. e68-e78 ◽  
Author(s):  
Christian Schmidl ◽  
Leo Hansmann ◽  
Timo Lassmann ◽  
Piotr J. Balwierz ◽  
Hideya Kawaji ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Type ◽  
Key Points ◽  
Cell Type Specific ◽  
Transcription Factor Networks ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Key Points Transcription and enhancer profiling reveal cell type–specific regulome architectures and transcription factor networks in conventional and regulatory T cells.

scholarly journals Adult Renal Stem/Progenitor Cells Can Modulate T Regulatory Cells and Double Negative T Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 274
Author(s):  
Claudia Curci ◽  
Angela Picerno ◽  
Nada Chaoul ◽  
Alessandra Stasi ◽  
Giuseppe De Palma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Double Negative ◽  
Chronic Injury ◽  
Peripheral Blood Mononuclear ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Adult Renal Stem/Progenitor Cells (ARPCs) have been recently identified in the human kidney and several studies show their active role in kidney repair processes during acute or chronic injury. However, little is known about their immunomodulatory properties and their capacity to regulate specific T cell subpopulations. We co-cultured ARPCs activated by triggering Toll-Like Receptor 2 (TLR2) with human peripheral blood mononuclear cells for 5 days and 15 days and studied their immunomodulatory capacity on T cell subpopulations. We found that activated-ARPCs were able to decrease T cell proliferation but did not affect CD8+ and CD4+ T cells. Instead, Tregs and CD3+ CD4- CD8- double-negative (DN) T cells decreased after 5 days and increased after 15 days of co-culture. In addition, we found that PAI1, MCP1, GM-CSF, and CXCL1 were significantly expressed by TLR2-activated ARPCs alone and were up-regulated in T cells co-cultured with activated ARPCs. The exogenous cocktail of cytokines was able to reproduce the immunomodulatory effects of the co-culture with activated ARPCs. These data showed that ARPCs can regulate immune response by inducing Tregs and DN T cells cell modulation, which are involved in the balance between immune tolerance and autoimmunity.

scholarly journals Disproportion in T-cell subpopulations in immunodeficient mutant hr/hr mice.

1979 ◽  
Vol 149 (1) ◽  
pp. 228-233 ◽  
Author(s):  
A B Reske-Kunz ◽  
M P Scheid ◽  
E A Boyse
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
Salient Feature ◽  
Mutant Gene ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Mice of the HRS strain, which carry the mutant gene hr, were examined for abnormalities in representation of the three T-cell sets Ly1, Ly23, and Ly123 in the spleen. The salient feature of hr/hr mice, which are immunologically deficient, in comparison with +/hr segregants, was a gross disproportion in numbers of cells belonging to the Ly1 and Ly123 sets, at the age of 3--3.5 mo. At this age, Ly123 cells of hr/hr spleen outnumbered Ly1 cells by 2:1, whereas in +/hr spleens Ly123 cells were outnumbered by approximately 1:2. Cells from pooled lymph nodes of hr/hr mice did not show a correspondingly gross disporprotion of Ly1 and Ly123 cells. Total counts of splenic T cells, and of B cells, were not significantly different in hr/hr and +/hr mice.

scholarly journals Selective expression of H-2 (i-region) loci controlling determinants on helper and suppressor T lymphocytes.

1976 ◽  
Vol 144 (3) ◽  
pp. 685-698 ◽  
Author(s):  
K Okumura ◽  
L A Herzenberg ◽  
D B Murphy ◽  
H O McDevitt ◽  
L A Herzenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Lymphoid Cells ◽  
Control Surface ◽  
Cell Subpopulation ◽  
Selective Expression ◽  
Suppressor T Lymphocytes ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Data presented here show that locidentify in the I-region of the H-2 gene complex are selectively expressed in different functional T-cell subpopulations. These loci are closely linked (or possibly identical) to loci that control immune responses. They control surface determinants which identify helper and suppressor T lymphocytes. Determinants described here on allotype suppressor T cells (Ts) are found on normal (nonsuppressed) lymphoid cells, but are not found on helper T cells (Th). These determinants are controlled by a locus mapping in the I region of the H-2 complex. In an accompanying publication we show that this locus (Ia-4) marks a new I subregion (I-J) and is expressed only on T cells. Thus Ia-4 determinants idenfity a T-cell subpopulation which includes Ts but not Th. Th also carry identifying surface determinants controlled by loci that map to the H-2 complex, probably within the I region. These determinants are not found on Ts. Data presented also establish that loci in the I region control determinants on Th, but do not conclusively demonstrate that these are the determinants that distinguish Th from Ts. The selective expression of H-2-controlled determinants on Ts and Th suggests that these determinants are directly involved in immunoregulation.

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