scholarly journals Schistosoma mansoni Larvae Do Not Expand or Activate Foxp3+Regulatory T Cells during Their Migratory Phase

2015 ◽  
Vol 83 (10) ◽  
pp. 3881-3889 ◽  
Author(s):  
Stephen A. Redpath ◽  
Nienke van der Werf ◽  
Andrew S. MacDonald ◽  
Rick M. Maizels ◽  
Matthew D. Taylor
Keyword(s):  
Schistosoma Mansoni ◽  
Treg Cell ◽  
Interleukin 10 ◽  
Treg Cells ◽  
Th2 Cells ◽  
Parasitic Helminth ◽  
Content Type ◽  
Cell Responses ◽  
Helminth Infections ◽  
Suppressive Cytokine

Foxp3+regulatory T (Treg) cells play a key role in suppression of immune responses during parasitic helminth infection, both by controlling damaging immunopathology and by inhibiting protective immunity. During the patent phase ofSchistosoma mansoniinfection, Foxp3+Treg cells are activated and suppress egg-elicited Th2 responses, but little is known of their induction and role during the early prepatent larval stage of infection. We quantified Foxp3+Treg cell responses during the first 3 weeks of murineS. mansoniinfection in C57BL/6 mice, a time when larval parasites migrate from the skin and transit the lungs en route to the hepatic and mesenteric vasculature. In contrast to other helminth infections,S. mansonidid not elicit a Foxp3+Treg cell response during this early phase of infection. We found that the numbers and proportions of Foxp3+Treg cells remained unchanged in the lungs, draining lymph nodes, and spleens of infected mice. There was no increase in the activation status of Foxp3+Treg cells upon infection as assessed by their expression of CD25, Foxp3, and Helios. Furthermore, infection failed to induce Foxp3+Treg cells to produce the suppressive cytokine interleukin 10 (IL-10). Instead, only CD4+Foxp3−IL-4+Th2 cells showed increased IL-10 production upon infection. These data indicate that Foxp3+Treg cells do not play a prominent role in regulating immunity toS. mansonilarvae and that the character of the initial immune response invoked byS. mansoniparasites contrasts with the responses to other parasitic helminth infections that promote rapid Foxp3+Treg cell responses.

Th2.rapa Cell Treatment of Established Murine Acute GVHD Is Abrogated by IL-2 Therapy and T Regulatory Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2169-2169
Author(s):  
Jason E. Foley ◽  
Jacopo Mariotti ◽  
Shoba Amarnath ◽  
Soo Han ◽  
Michael Eckhaus ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Treg Cell ◽  
Treg Cells ◽  
Th2 Cells ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Cell Product ◽  
Cell Responses ◽  
Th2 Cell ◽  
Ifn Γ

Abstract Rapamycin-generated donor Th2 cells attenuate established acute murine GVHD (Foley et al, JI, 2005) and are dependent in part upon IL-4 and IL-10 secretion (ASBMT Meeting, 2007). That is, Th2.rapa cell recipients (Th2 infusion, d 14 post-BMT) had increased survival relative to GVHD controls (post-BMT survival, median days; 33.7±0.4 vs. 24.8±1.2; p=0.0002) whereas recipients of IL-4 or IL-10 knockout Th2.rapa cells did not have increased survival (28.9±0.3 and 24.6±0.2 days, respectively; p=NS). These data indicate that Th2.rapa cells operate through a Th2-type mechanism rather than a Treg cell mechanism; in addition, we found that Th2.rapa cells expressed low levels of the Treg cell transcription factor, Foxp3 (<5% CD4+Foxp3+). Additional experiments were performed to further investigate a potential role of Treg cell biology to Th2.rapa cell therapy. First, we hypothesized that IL-2 therapy may promote Th2.rapa cell expansion and efficacy in a manner analogous to IL-2 promotion of Treg cell responses in vivo. Second, we hypothesized that enrichment of the Th2.rapa cell product with natural (unmanipulated) Treg cells may enhance an anti-GVHD effect. Contrary to our first hypothesis, we found that IL-2 therapy (50,000 IU bid; d14–18 post-BMT) reduced the number of splenic Th2.rapa cells at d 19 post-BMT (CD90.1-marked cells, million [M]/spleen; 5.0±0.4 [no IL-2] vs. 2.3±0.4 [+IL-2]; p=<0.001) and increased the number of unmanipulated donor CD4+ cells (CD45.2-marked cells, M/spleen; 16.6±0.7 [no IL-2] vs. 26.6±2.4 [+IL-2]; p=0.004) and CD8+ cells (15.9±1.7 [no IL-2] vs. 23.9±2.4 [+IL-2]; p=0.03). IL-2 therapy also inhibited Th2.rapa cell-mediated cytokine polarization (d 19 post-BMT, pg/ml; IL-4 reduced from 3501±179 [no IL-2] to 1116±261 [+IL-2], p=<0.0001; IL-10 reduced from 707±56 [no IL-2] to 288±37 [+IL-2], p=0.0002; and IFN-γ increased from 81±22 [no IL-2] to 320±97 [+IL-2], p=0.042). Importantly, for Th2.rapa cell recipients, IL-2 therapy reduced post-BMT survival (d post-BMT; 42.0±0.5 [no IL-2] vs. 33.8±1.0 [+IL-2], p=<0.0001). With regard to our second hypothesis, we found that addition of Treg cells to the Th2.rapa cell product (Treg to Th2.rapa cell ratio, 1:10) reduced the number of Th2.rapa cells at d 19 post-BMT (M/spleen; 16.6±1.3 [no Treg] vs. 7.9±1.2 [+ Treg], p=0.0012) and increased the number of unmanipulated donor CD4+ cells (M/spleen; 12.4±0.7 [no Treg] vs. 20.7±0.8 [+Treg], p=<0.0001) and CD8+ cells (M/spleen; 8.4±0.8 [no Treg] vs. 16.1±1.4 [+Treg], p= 0.0014). Treg cell co-infusion also inhibited Th2.rapa cell-mediated cytokine polarization (d 19 post-BMT, pg/ml; IL-4 reduced from 497±47 [no Treg] to 100±15 [+ Treg]; p=<0.0001); IL-10 reduced from 160±32 [no Treg] to 27±7 [+Treg]; p= 0.004; and IFN-γ increased from 83±5 [no Treg] to 230±40 [+Treg]; p=0.006). Finally, for Th2.rapa cell recipients, co-infusion of Treg cells reduced post-BMT survival (median d post-BMT; 44.2±1.1 [no Treg] vs. 30.7±1.3 [+Treg]; p=0.0002). In conclusion, interventions that promote Treg cell responses, namely infusion of IL-2 and co-administration of natural Treg cells, reduce Th2.rapa cell promotion of IL-4 and IL-10 post-BMT and reduce the Th2 cell-mediated survival advantage against established GVHD. Because IL-4 and IL-10 are required for Th2.rapa cell therapy of GVHD in this model, these new data indicate that Treg cells abrogate Th2.rapa cell therapy by inhibiting the Th2 cell effector response.

scholarly journals PD-L1 – PD-1 interactions limit effector Treg cell populations at homeostasis and during infection

2020 ◽  
Author(s):  
J.A. Perry ◽  
J.T. Clark ◽  
J. Gullicksrud ◽  
J. DeLong ◽  
L. Shallberg ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cell ◽  
Cell Activity ◽  
T Cell Responses ◽  
Treg Cells ◽  
Whole Body ◽  
Cell Responses ◽  
Early Production ◽  
Ifn Γ ◽  
Specific Deletion

AbstractWhile much is known about the factors that promote the development of diverse Treg cell responses, less is known about the pathways that constrain Treg cell activities. The studies presented here reveal that at homeostasis there is a population of effector Treg cells that express PD-1, and that blockade of PD-L1 or loss of PD-1 results in increased Treg cell activity. In response to infection with the parasite T. gondii, the early production of IFN-γ results in widespread upregulation of PD-L1. Moreover, blockade of PD-L1, whole body deletion of PD-1, or lineage-specific deletion of PD-1 in Foxp3+ cells prevented the loss of the effector Treg cells but resulted in reduced pathogen specific CD4+ T cell responses during infection. Thus, at homeostasis basal PD-L1 expression constrains and tunes the pool of Treg cells, but during infection the upregulation of PD-L1 provides a mechanism to contract the Treg cell population required to maximize the development of pathogen specific CD4+ T cell responses.

scholarly journals Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 38 ◽  
Author(s):  
Azza Abdel-Gadir ◽  
Amir H. Massoud ◽  
Talal A. Chatila
Keyword(s):  
Immune Responses ◽  
Treg Cell ◽  
Allergic Diseases ◽  
Treg Cells ◽  
Immunological Tolerance ◽  
Inflammatory Disorders ◽  
Cell Responses ◽  
Recent Advances ◽  
And Function ◽  
Is Failure

Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders.

scholarly journals CD4+T Cell Hyporesponsiveness after Repeated Exposure to Schistosoma mansoni Larvae Is Dependent upon Interleukin-10

2015 ◽  
Vol 83 (4) ◽  
pp. 1418-1430 ◽  
Author(s):  
Catriona T. Prendergast ◽  
David E. Sanin ◽  
Peter C. Cook ◽  
Adrian P. Mountford
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Schistosoma Mansoni ◽  
Interleukin 2 ◽  
Interleukin 10 ◽  
Multiple Infections ◽  
Content Type ◽  
Key Factor

The effect that multiple percutaneous exposures toSchistosomalarvae has on the development of early CD4+lymphocyte reactivity is unclear, yet it is important in the context of humans living in areas where schistosomiasis is endemic. In a murine model of multiple infections, we show that exposure of mice to repeated doses (4×) ofSchistosoma mansonicercariae, compared to a single dose (1×), results in CD4+T cell hyporesponsiveness within the skin-draining lymph nodes (sdLN), manifested as reduced CD4+cell proliferation and cytokine production. FoxP3+CD4+regulatory T cells were present in similar numbers in the sdLN of 4× and 1× mice and thus are unlikely to have a role in effecting hyporesponsiveness. Moreover, anergy of the CD4+cell population from 4× mice was slight, as proliferation was only partly circumvented through thein vitroaddition of exogenous interleukin-2 (IL-2), and thein vivoblockade of the regulatory molecule PD1 had a minimal effect on restoring responsiveness. In contrast, IL-10 was observed to be critical in mediating hyporesponsiveness, as CD4+cells from the sdLN of 4× mice deficient for IL-10 were readily able to proliferate, unlike those from 4× wild-type cohorts. CD4+cells from the sdLN of 4× mice exhibited higher levels of apoptosis and cell death, but in the absence of IL-10, there was significantly less cell death. Combined, our data show that IL-10 is a key factor in the development of CD4+T cell hyporesponsiveness after repeated parasite exposure involving CD4+cell apoptosis.

scholarly journals Function of regulatory T-cells improved by dexamethasone in Graves' disease

2012 ◽  
Vol 166 (4) ◽  
pp. 641-646 ◽  
Author(s):  
Yun Hu ◽  
Wei Tian ◽  
Ling-Ling Zhang ◽  
Hao Liu ◽  
Guo-Ping Yin ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Treg Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Treg Cells ◽  
Th2 Cells ◽  
Graves Disease ◽  
Treg Cell Function

ObjectiveIntrathyroid injection of dexamethasone (DEX) has been used to treat Graves' disease (GD); however, the mechanism of this treatment remains poorly understood. The objective of this study was to investigate the effects of DEX on the function of regulatory T (Treg) cells (CD4+CD25+T cells) in patients with GD.MethodsPeripheral blood was obtained from 20 patients with GD, and peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll–Hypaque density gradient separation. CD4+CD25–/CD4+CD25+T cells were isolated by immunomagnetic selection and DEX was co-cultured with PBMCs or isolated T-cells for 72 h. Treg cell function was analyzed using the proliferation rate of CD4+CD25–T cells.ResultsThe proportion of Treg cells and the transcription factor forkhead box P3 (FOXP3) mRNA expression in PBMCs decreased in GD patients compared with healthy subjects, and Treg cell function was impaired in patients with GD. Although the proportion of Treg cells and FOXP3 mRNA expression in PBMCs did not increase, the function of Treg cells improved after the treatment with DEX. Moreover, the proportion of T-helper 2 (Th2) cells was decreased by the DEX treatment.ConclusionsDEX could effectively improve the function of Treg cells and set up a new balance of Th1/Th2 in GD patients. This study might help to further understand the immune mechanism of the intrathyroid injection of DEX in the treatment of GD and facilitate the potential use of this therapy.

scholarly journals The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Agnieszka M Kabat ◽  
Oliver J Harrison ◽  
Thomas Riffelmacher ◽  
Amin E Moghaddam ◽  
Claire F Pearson ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Treg Cells ◽  
Th2 Cells ◽  
Metabolic Adaptation ◽  
Cell Responses ◽  
Th2 Cell ◽  
Autophagy Gene ◽  
Th Cell ◽  
Inflammatory Bowel

A polymorphism in the autophagy gene Atg16l1 is associated with susceptibility to inflammatory bowel disease (IBD); however, it remains unclear how autophagy contributes to intestinal immune homeostasis. Here, we demonstrate that autophagy is essential for maintenance of balanced CD4+ T cell responses in the intestine. Selective deletion of Atg16l1 in T cells in mice resulted in spontaneous intestinal inflammation that was characterized by aberrant type 2 responses to dietary and microbiota antigens, and by a loss of Foxp3+ Treg cells. Specific ablation of Atg16l1 in Foxp3+ Treg cells in mice demonstrated that autophagy directly promotes their survival and metabolic adaptation in the intestine. Moreover, we also identify an unexpected role for autophagy in directly limiting mucosal TH2 cell expansion. These findings provide new insights into the reciprocal control of distinct intestinal TH cell responses by autophagy, with important implications for understanding and treatment of chronic inflammatory disorders.

Dysfunctional T Regulatory Cells in Myeloma: Molecular Mechanisms of Dysregulation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3462-3462
Author(s):  
Rao H. Prabhala ◽  
Paola Neri ◽  
Pierfrancesco Tassone ◽  
Jooeun E. Bae ◽  
Masood A. Shammas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Cell Activity ◽  
T Cell Responses ◽  
Treg Cells ◽  
Cell Responses ◽  
Treg Cell Function

Abstract Multiple myeloma (MM) is characterized by production of monoclonal immunoglobulin, associated with suppressed uninvolved immunoglobulins and dysfunctional T cell responses. The biological basis of this dysfunction remains ill defined. Since T regulatory (Treg) cells play an important role in suppressing normal immune responses, we have here evaluated the potential role of Treg cells in immune dysfunction in MM. We observed a significant increase in CD4+CD25+ T cells in individuals with monoclonal gammopathy of undetermined significance (MGUS) and patients with MM compared to normal donors (25% and 26% versus 14%, respectively); however, Treg cells as measured by Foxp3 expression are significantly decreased in both MGUS (1.6±0.5%, p&lt;0.01) and MM (1.6±0.5%, p&lt;0.01) compared to normal donors (6.0±0.8%). Additionally, these Treg cells also do not function normally. Treg cells from patients with MM and MGUS even when added in higher proportions are unable to suppress anti-CD3-mediated T cell proliferation. This decreased number and function of Treg cells in MGUS and in MM may account, at least in part, for the non-specific increase in CD4+CD25+ T cells, thereby contributing to dysfunctional T cell responses. We have further analyzed the molecular basis for the Treg cell dysfunction in myeloma. Based on the preliminary results suggesting a role of IL-6 in Treg cell function and since both serum IL-6 and soluble IL-6 receptor levels are significantly elevated in MGUS and MM, we evaluated the role of IL-6 and its soluble receptor on Treg cell function. We observed that the addition of IL-6 and/or sIL-6 receptor to the culture leads to loss of Treg cell activity in normal donor cells similar to one observed in myeloma patients; and conversely, when Treg cells from MM patients are treated with the anti-IL-6 antibody or IL-6 receptor super antagonist, sant 7, the suppressive activity of Treg cells is restored. Additionally, we have preliminary evidence of expansion of Foxp3+ cell numbers in PBMC from MM patients following in vitro treatment with anti-IL-6 antibody. This data suggests a role of IL-6 and bone marrow microenvironment in dysfunctional Treg cells in MM and that inhibition of IL-6 signaling results in beneficial effects on T cell activity by increasing Treg cell activity. A blockade of IL-6 signaling thus emerges as a potential approach to establish immune homeostasis to improve immune function in MM.

scholarly journals Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool

2021 ◽  
Author(s):  
Marc Permanyer ◽  
Berislav Bošnjak ◽  
Silke Glage ◽  
Michaela Friedrichsen ◽  
Stefan Floess ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Interleukin 2 ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Receptor Expression ◽  
Spontaneous Mutant ◽  
Cell Pool ◽  
And Function

AbstractSignaling via interleukin-2 receptor (IL-2R) is a requisite for regulatory T (Treg) cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function in both resting and inflammatory conditions. Here, we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25, the α-chain of IL-2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under noninflammatory conditions, Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease. In contrast, Cd25Y129H Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with the maintenance, heterogeneity, and suppressive function of the Treg cell pool.

Regulation of IL-17 in chronic inflammation in the human lung

2011 ◽  
Vol 120 (12) ◽  
pp. 515-524 ◽  
Author(s):  
Carol Pridgeon ◽  
Laurence Bugeon ◽  
Louise Donnelly ◽  
Ursula Straschil ◽  
Susan J. Tudhope ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Tissue ◽  
Mononuclear Cells ◽  
Human Lung ◽  
Treg Cells ◽  
Orphan Receptor ◽  
Th2 Cells ◽  
Chronic Obstructive ◽  
Interleukin 17

The regulation of human Th17 cell effector function by Treg cells (regulatory T-cells) is poorly understood. In the present study, we report that human Treg (CD4+CD25+) cells inhibit the proliferative response of Th17 cells but not their capacity to secrete IL (interleukin)-17. However, they could inhibit proliferation and cytokine production by Th1 and Th2 cells as determined by IFN-γ (interferon-γ) and IL-5 biosynthesis. Currently, as there is interest in the role of IL-17-producing cells and Treg cells in chronic inflammatory diseases in humans, we investigated the presence of CD4+CD25+ T-cells and IL-17 in inflammation in the human lung. Transcripts for IL-17 were expressed in mononuclear cells and purified T-cells from lung tissue of patients with chronic pulmonary inflammation and, when activated, these cells secrete soluble protein. The T-cell-specific transcription factors RORCv2 (retinoic acid-related orphan receptor Cv2; for Th17) and FOXP3 (forkhead box P3; for Treg cells) were enriched in the T-cell fraction of lung mononuclear cells. Retrospective stratification of the patient cohort into those with COPD (chronic obstructive pulmonary disease) and non-COPD lung disease revealed no difference in the expression of IL-17 and IL-23 receptor between the groups. We observed that CD4+CD25+ T-cells were present in comparable numbers in COPD and non-COPD lung tissue and with no correlation between the presence of CD4+CD25+ T-cells and IL-17-producing cells. These results suggest that IL-17-expressing cells are present in chronically inflamed lung tissue, but there is no evidence to support this is due to the recruitment or expansion of Treg cells.

scholarly journals Characterization of T Cells Specific for CFP-10 and ESAT-6 in Mycobacterium tuberculosis-Infected Mauritian Cynomolgus Macaques

2017 ◽  
Vol 85 (4) ◽  
Author(s):  
Amy Ellis ◽  
Alexis Balgeman ◽  
Mark Rodgers ◽  
Cassaundra Updike ◽  
Jaime Tomko ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mhc Class Ii ◽  
Nonhuman Primates ◽  
Content Type ◽  
Host Immune Responses ◽  
Cell Responses ◽  
Cynomolgus Macaques ◽  
Mhc Haplotype

ABSTRACT Nonhuman primates can be used to study host immune responses to Mycobacterium tuberculosis. Mauritian cynomolgus macaques (MCMs) are a unique group of animals that have limited major histocompatibility complex (MHC) genetic diversity, such that MHC-identical animals can be infected with M. tuberculosis. Two MCMs homozygous for the relatively common M1 MHC haplotype were bronchoscopically infected with 41 CFU of the M. tuberculosis Erdman strain. Four other MCMs, which had at least one copy of the M1 MHC haplotype, were infected with a lower dose of 3 CFU M. tuberculosis. All animals mounted similar T-cell responses to CFP-10 and ESAT-6. Two epitopes in CFP-10 were characterized, and the MHC class II alleles restricting them were determined. A third epitope in CFP-10 was identified but exhibited promiscuous restriction. The CFP-10 and ESAT-6 antigenic regions targeted by T cells in MCMs were comparable to those seen in cases of human M. tuberculosis infection. Our data lay the foundation for generating tetrameric molecules to study epitope-specific CD4 T cells in M. tuberculosis-infected MCMs, which may guide future testing of tuberculosis vaccines in nonhuman primates.

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