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

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.

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The Worm-Specific Immune Response in Multiple Sclerosis Patients Receiving Controlled Trichuris suis Ova Immunotherapy

Life ◽

10.3390/life11020101 ◽

2021 ◽

Vol 11 (2) ◽

pp. 101

Author(s):

Ivet A. Yordanova ◽

Friederike Ebner ◽

Axel Ronald Schulz ◽

Svenja Steinfelder ◽

Berit Rosche ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

Clinical Efficacy ◽

Mononuclear Cells ◽

Phase 1 ◽

Th2 Cells ◽

Continuous Increase ◽

Trichuris Suis ◽

Multiple Sclerosis Patients

Considering their potent immunomodulatory properties, therapeutic applications of Trichuris suis ova (TSO) are studied as potential alternative treatment of autoimmune disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), or inflammatory bowel disease (IBD). Clinical phase 1 and 2 studies have demonstrated TSO treatment to be safe and well tolerated in MS patients, however, they reported only modest clinical efficacy. We therefore addressed the cellular and humoral immune responses directed against parasite antigens in individual MS patients receiving controlled TSO treatment (2500 TSO p.o. every 2 weeks for 12 month). Peripheral blood mononuclear cells (PBMC) of MS patients treated with TSO (n = 5) or placebo (n = 6) were analyzed. A continuous increase of serum IgG and IgE antibodies specific for T. suis excretory/secretory antigens was observed up to 12 months post-treatment. This was consistent with mass cytometry analysis identifying an increase of activated HLA-DRhigh plasmablast frequencies in TSO-treated patients. While stable and comparable frequencies of total CD4+ and CD8+ T cells were detected in placebo and TSO-treated patients over time, we observed an increase of activated HLA-DR+CD4+ T cells in TSO-treated patients only. Frequencies of Gata3+ Th2 cells and Th1/Th2 ratios remained stable during TSO treatment, while Foxp3+ Treg frequencies varied greatly between individuals. Using a T. suis antigen-specific T cell expansion assay, we also detected patient-to-patient variation of antigen-specific T cell recall responses and cytokine production. In summary, MS patients receiving TSO treatment established a T. suis-specific T- and B-cell response, however, with varying degrees of T cell responses and cellular functionality across individuals, which might account for the overall miscellaneous clinical efficacy in the studied patients.

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T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1522287113 ◽

2016 ◽

Vol 113 (5) ◽

pp. E568-E576 ◽

Cited By ~ 10

Author(s):

Jimena Perez-Lloret ◽

Isobel S. Okoye ◽

Riccardo Guidi ◽

Yashaswini Kannan ◽

Stephanie M. Coomes ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Allergic Diseases ◽

Treg Cells ◽

Th2 Cells ◽

T Helper 2 ◽

Cytokines And Chemokines ◽

Th2 Cell

There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ+CD4+ T-helper 2 (TH2) cells orchestrate the type-2–driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081–E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4gfp+αβ+CD4+ TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell–intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24−/− T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1–regulated signaling. Following this prediction, we found that Trim24−/− T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β–mediated activation in vitro and in vivo, and fail to respond to IL-1β–exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell–intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.

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Daclizumab reduces CD25 levels on T cells through monocyte-mediated trogocytosis

Multiple Sclerosis Journal ◽

10.1177/1352458513494488 ◽

2013 ◽

Vol 20 (2) ◽

pp. 156-164 ◽

Cited By ~ 16

Author(s):

Y Zhang ◽

M McClellan ◽

L Efros ◽

D Shi ◽

B Bielekova ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mononuclear Cells ◽

Interleukin 2 ◽

Treg Cells ◽

Activated T Cells ◽

Peripheral Blood Mononuclear ◽

Dependent Relationship ◽

Cell Counts ◽

Humanized Monoclonal Antibody

Daclizumab is a humanized monoclonal antibody that prevents interleukin-2 (IL-2) binding to CD25, blocking IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating daclizumab as a treatment for multiple sclerosis (MS) included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between daclizumab and reductions in HLA-DR+-activated T cells, a similar relationship was not observed for reductions in CD25 levels. The objective of this report is to determine the mechanism by which daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMCs) using cytometric techniques. Daclizumab reduced T cell CD25 levels through a mechanism that required the daclizumab-Fc domain interaction with Fc receptors (FcR) on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4+ T cells and FoxP3+ Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of PBMCs. In conclusion, Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signaling.

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Donor T Cell Production of IL-21 Accelerates Graft-Versus-Host Disease Lethality.

Blood ◽

10.1182/blood.v112.11.2342.2342 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2342-2342

Author(s):

Christoph Bucher ◽

Christine Vogtenhuber ◽

Lisa Jasperson ◽

Angela Panoskaltsis-Mortari ◽

Emily Goren ◽

...

Keyword(s):

Weight Loss ◽

T Cells ◽

T Cell ◽

Mononuclear Cells ◽

Bone Marrow Cells ◽

Histopathological Examination ◽

Treg Cells ◽

Gamma Chain ◽

Term Survival ◽

Mean Values

Abstract IL-21, produced by T-cells, binds to the common gamma chain family member, IL21R, expressed on immune and colonic epithelial cells. IL-21 signaling results in the maturation, activation and proliferation of T, B, NK-cells and DCs. IL-21 has been implicated in Th17 generation/amplification and also modulating Treg differentiation. However, the relevance of this in disease is unclear. Therefore, we wanted to study the effects of IL-21 depletion and the role of Th17 and Treg cells in the context of GVHD. A lethally irradiated, complete MHC disparate model (B6 to B10.BR) using donor bone marrow cells alone or with the addition of wild-type (wt) CD4+CD25- Effector T-cells and irrelevant or anti-IL-21 Ab from days 0 to 25 twice per week. The administration of anti-IL-21Ab lead to a significant delay of weight loss and mortality (P<0.0001). To determine whether IL-21 deficiency accelerates or inhibits GVHD, studies were performed comparing GVHD-inducing ability of wt or IL-21 knockout (IL21−/−) donor CD4+CD25- T cells. A striking survival advantage of recipients of IL-21−/− vs wt CD4+CD25- T cells was observed (100% vs 0% surviving, P < 0.0001). Subsequent studies were performed using whole T cells, a more clinically relevant donor T cell graft source. Whereas recipients of wt T-cells all died of GvHD within 50 days of GvHD, recipients of IL-21 −/− T-cells showed significantly less weight loss and superior long-term survival (P < 0.0001). Histopathological examination of recipients of CD25-depleted T-cells on d14 revealed significantly reduced GvHD scores of the colonic mucosa and a trend towards lower GvHD scores in the small intestine, liver and the spleen in recipients of IL-21−/− cells. Although flow cytometry analysis of mononuclear cells showed no changes in the frequency of IL-17 producing cells in spleen, liver and colon, the frequency of interferon gamma producing CD4+ T- (Th1) cells was significantly lower in the spleen and the colon of recipients of IL-21−/− vs. wt T-cells. Moreover, increased Treg frequencies were seen in the colon of IL-21−/− vs wt CD25-depleted T cells (mean values: 7.5% vs. 2.1%; P < 0.003). We conclude that IL-21 production by either CD25- depleted T-cells or CD4+CD25- T cells is sufficient to increase GVHD mortality and that Treg inhibition, rather than Th17 generation or amplification, are likely contributing to GVHD lethality acceleration. We also conclude that IL-21 neutralization represents a novel approach for GVHD inhibition that warrants further investigation.

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CD69 Association with Jak3/Stat5 Proteins Regulates Th17 Cell Differentiation

Molecular and Cellular Biology ◽

10.1128/mcb.00456-10 ◽

2010 ◽

Vol 30 (20) ◽

pp. 4877-4889 ◽

Cited By ~ 70

Author(s):

Pilar Martín ◽

Manuel Gómez ◽

Amalia Lamana ◽

Arantxa Cruz-Adalia ◽

Marta Ramírez-Huesca ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

T Cell ◽

Th17 Cells ◽

T Cell Differentiation ◽

Orphan Receptor ◽

Interleukin 17 ◽

Deficient Mice

ABSTRACT T-cell differentiation involves the early decision to commit to a particular pattern of response to an antigen. Here, we show that the leukocyte activation antigen CD69 limits differentiation into proinflammatory helper T cells (Th17 cells). Upon antigen stimulation in vitro, CD4+ T cells from CD69-deficient mice generate an expansion of Th17 cells and the induction of greater mRNA expression of interleukin 17 (IL-17), IL 23 receptor (IL-23R), and the nuclear receptor retinoic acid-related orphan receptor γt (RORγt). In vivo studies with CD69-deficient mice bearing OTII T-cell receptors (TCRs) specific for OVA peptide showed a high proportion of antigen-specific Th17 subpopulation in the draining lymph nodes, as well as in CD69-deficient mice immunized with type II collagen. Biochemical analysis demonstrated that the CD69 cytoplasmic tail associates with the Jak3/Stat5 signaling pathway, which regulates the transcription of RORγt and, consequently, differentiation toward the Th17 lineage. Functional experiments in Th17 cultures demonstrated that the selective inhibition of Jak3 activation enhanced the transcription of RORγt. Moreover, the addition of exogenous IL-2 restored Stat5 phosphorylation and inhibited the enhanced Th17 differentiation in CD69-deficient cells. These results support the early activation receptor CD69 as an intrinsic modulator of the T-cell differentiation program that conditions immune inflammatory processes.

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Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma

Blood ◽

10.1182/blood-2007-08-105395 ◽

2008 ◽

Vol 111 (11) ◽

pp. 5359-5370 ◽

Cited By ~ 85

Author(s):

Sajjan Mittal ◽

Neil A. Marshall ◽

Linda Duncan ◽

Dominic J. Culligan ◽

Robert N. Barker ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hodgkin Lymphoma ◽

Tumor Cells ◽

Cd4 T Cells ◽

Mononuclear Cells ◽

Treg Cells ◽

Disease Stage ◽

Serum Lactate Dehydrogenase ◽

Non Hodgkin Lymphoma

Abstract Regulatory T (Treg) cells contribute to immune evasion by malignancies. To investigate their importance in non-Hodgkin lymphoma (NHL), we enumerated Treg cells in peripheral blood mononuclear cells (PBMCs) and involved tissues from 30 patients. CD25+FoxP3+CD127lowCD4+ Treg cells were increased markedly in PBMCs (median = 20.4% CD4 T cells, n = 20) versus healthy controls (median = 3.2%, n = 13, P < .001) regardless of lymphoma subtype, and correlated with disease stage and serum lactate dehydrogenase (Rs = 0.79, P < .001). T-cell hyporesponsiveness was reversed by depleting CD25+ cells, or by adding anti–CTLA-4, supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. A high proportion of Treg cells was also present in involved tissues (median = 38.8% CD4 T cells, n = 15) versus reactive nodes (median = 11.6%, n = 2, P = .02). When autologous CD25− PBMC fractions were incubated with tumor cells from patients (n = 6) in vitro, there was consistent strong induction and then expansion of cells with the CD4+CD25+FoxP3+ phenotype of classic “natural” Treg cells. This population was confirmed to be suppressive in function. Direct cell-cell interaction of tumor cells with CD25− PBMCs was important in Treg induction, although there was heterogeneity in the mechanisms responsible. We conclude that NHL cells are powerful inducers of Treg cells, which may represent a new therapeutic target.

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Effects of Telbivudine Treatment on the Circulating CD4+T-Cell Subpopulations in Chronic Hepatitis B Patients

Mediators of Inflammation ◽

10.1155/2012/789859 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 18

Author(s):

Yanhua Zheng ◽

Zemin Huang ◽

Xianhua Chen ◽

Yi Tian ◽

Jun Tang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hepatitis B ◽

Antiviral Agents ◽

Adaptive Immune Response ◽

Treg Cells ◽

T Cell Subsets ◽

Th2 Cells ◽

Th1 Cell ◽

T Cell Subpopulations

CD4+T cells serve as master regulators of the adaptive immune response to HBV. However, CD4+T-cell subsets are heterogeneous, and it remains unknown how the antiviral agents affect the different CD4+T cell subtypes. To this end, the expressions of signature transcription factors and cytokines of CD4+T-cell subtypes were examined in hepatitis B patients before and after treatment with telbivudine. Results showed that, upon the rapid HBV copy decrease induced by telbivudine treatment, the frequencies and related cytokines of Th17 and Treg cells were dramatically decreased, while those for Th2 cells were dramatically increased. No obvious changes were observed in Th1 cell frequencies; although, IFN-γexpression was upregulated in response to telbivudine treatment, suggesting another cell source of IFN-γin CHB patients. Statistical analyses indicated that Th17 and Tr1 (a Treg subtype) cells were the most sensitive subpopulations of the peripheral blood CD4+T cells to telbivudine treatment over 52 weeks. Thus, Th17 and Tr1 cells may represent a suitable and effective predictor of responsiveness during telbivudine therapy. These findings not only improve our understanding of hepatitis pathogenesis but also can aid in future development of appropriate therapeutic strategies to control viral hepatitis.

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Kuijieling-Containing Serum Regulates Th17 and Treg Cell Differentiation by Inhibiting STAT3 Signaling In Vitro

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/7837989 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9

Author(s):

Yu Long ◽

Yuqing He ◽

Fengming Jie ◽

Sixin Li ◽

Yanli Wu ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

Mononuclear Cells ◽

Transforming Growth Factor ◽

Treg Cells ◽

Orphan Receptor ◽

Cell Culture Supernatant ◽

T Helper 17 ◽

Peripheral Blood Mononuclear

Object. To investigate the effect of Kuijieling (KJL) on the balance between T helper 17 (Th17) and regulatory T (Treg) cells in peripheral blood mononuclear cells (PBMC) in vitro and explore the underlying mechanism. Materials and Methods. PBMCs isolated from rats were stimulated with transforming growth factor-β, interleukin (IL)-6, and IL-23 to induce the imbalance of Th17 and Treg cells and were treated with 10, 5, or 2.5% KJL-containing serum. The proportion of Th17 or Treg cells in CD4+ T cells was analyzed by flow cytometry, the concentrations of IL-17, IL-21, and IL-10 were assayed by ELISA, mRNA expressions of retinoic acid-related orphan receptor γt (RORγt), forkhead box protein 3 (Foxp3), and signal transducer and activator of transcription 3 (STAT3) were quantified by PCR, and phosphorylated STAT3 (p-STAT3) was analyzed by flow cytometry. Results. KJL-containing serum decreased the proportion of Th17 cells and increased the proportion of Treg cells in CD4+ T cells, decreased the concentration of IL-17 and IL-21, enhanced the level of IL-10 in the cell culture supernatant, promoted the expression of Foxp3, and inhibited the levels of RORγt, STAT3, and p-STAT3. Conclusion. KJL suppresses the STAT3 pathway to remedy the imbalance between Th17 and Treg cells.

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Elastin receptor (S-gal) occupancy by elastin peptides modulates T-cell response during murine emphysema

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00465.2016 ◽

2017 ◽

Vol 313 (3) ◽

pp. L534-L547 ◽

Cited By ~ 6

Author(s):

Aïda Meghraoui-Kheddar ◽

Alexandre Pierre ◽

Mehdi Sellami ◽

Sandra Audonnet ◽

Flora Lemaire ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Ex Vivo ◽

Binding Protein ◽

T Cell Response ◽

Orphan Receptor ◽

Cell Subpopulation ◽

Chronic Obstructive

Chronic obstructive pulmonary disease and emphysema are associated with increased elastin peptides (EP) production because of excessive breakdown of lung connective tissue. We recently reported that exposure of mice to EP elicited hallmark features of emphysema. EP effects are largely mediated through a receptor complex that includes the elastin-binding protein spliced-galactosidase (S-gal). In previous studies, we established a correlation between cytokine production and S-gal protein expression in EP-treated immune cells. In this study, we investigated the S-gal-dependent EP effects on T-helper (Th) and T-cytotoxic (Tc) responses during murine EP-triggered pulmonary inflammation. C57BL/6J mice were endotracheally instilled with the valine-glycine-valine-alanine-proline-glycine (VGVAPG) elastin peptide, and, 21 days after treatment, local and systemic T-lymphocyte phenotypes were analyzed at cytokine and transcription factor expression levels by multicolor flow cytometry. Exposure of mice to the VGVAPG peptide resulted in a significant increase in the proportion of the CD4+ and CD8+ T cells expressing the cytokines IFN-γ or IL-17a and the transcription factors T-box expressed in T cells or retinoic acid-related orphan receptor-γt (RORγt) without effects on IL-4 and Gata-binding protein 3 to DNA sequence [A/T]GATA[A/G] expression. These effects were maximized when each T-cell subpopulation was challenged ex vivo with EP, and they were inhibited in vivo when an analogous peptide antagonizing the EP/S-gal interactions was instilled together with the VGVAPG peptide. This study demonstrates that, during murine emphysema, EP-S-gal interactions contribute to a Th-1 and Th-17 proinflammatory T-cell response combined with a Tc-1 response. Our study also highlights the S-gal receptor as a putative pharmacological target to modulate such an immune response.

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Abstract TP460: Regulatory T-Cells and CD4+ T Helper Cell Subsets Are Differentially Regulated and Express Distinct Activation States After Aneurysmal Subarachnoid Hemorrhage (SAH) and During Post-SAH Complications

Stroke ◽

10.1161/str.51.suppl_1.tp460 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Shafqat R Chaudhry ◽

Sajjad Muhammad

Keyword(s):

T Cells ◽

Subarachnoid Hemorrhage ◽

T Cell ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Treg Cells ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Th2 Cells ◽

T Helper ◽

Hla Dr

Background: Aneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Devastating post-SAH complications after aneurysm treatment lead to poor clinical outcome. Current research suggests critical role of inflammation during early and delayed brain injury phases over which these complications arise. T helper cells can polarize to multiple functionally unique subsets. Here, we investigate different CD4+ T cell subsets during these brain injury phases after SAH and their dynamics during post-SAH complications. Methods: Anticoagulated peripheral venous blood was obtained from 15 SAH patients on days 1 and 7, and once from healthy controls. After erythrocyte lysis and single cell wash, 1 million cells were stained with different anti-human mouse monoclonal antibodies and were acquired on BD LSR Fortessa. Lymphocytes were gated based on low side scatter and high CD45 expression. Different CD3+CD4+ T cell subsets were characterized by differential cell surface expression of CXCR3 and CCR6 into Th1, Th2, Th17, whereas Tregs by CD25 hi and CD127 lo . SAH patients were dichotomized based on presence or absence of different post-SAH complications (hydrocephalus, seizures, CVS, cerebral ischemia) to assess association of T cell subsets with these complications. Results: Total CD4+ T cells were significantly increased after SAH. Interestingly, Th2 cells were significantly decreased and Th17 cells increased on day 7 compared to day 1 after SAH. However, regulatory T-cells were significantly increased on both assessment days compared to controls. The analysis of activation states was done by CD38 and HLA-DR expression. Th1 and Treg cells were significantly increased on day 1 in SAH patients who developed seizures and CVS, respectively. HLA-DR + CD38 + Th2 cells significantly increased on day 1 in SAH patients who developed hydrocephalus, whereas HLA-DR - CD38 - Th1 cells significantly increased on day 1 in patients with infections. HLA-DR - CD38 - Treg cells were significantly reduced on day 1 and day 7 in patients developing cerebral ischemia . Conclusion: CD4+ T cell subsets and Treg cells display dynamic patterns after SAH, and show a distinct pattern of polarization and activation states in specific post-SAH complications.

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