scholarly journals Regulatory T cell expansion by a highly CD25-dependent IL-2 mutein arrests ongoing autoimmunity

2019 ◽  
Author(s):  
Liliane Khoryati ◽  
Minh Nguyet Pham ◽  
McKenna Sherve ◽  
Swarnima Kumari ◽  
Kevin Cook ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Dose Range ◽  
Interleukin 2 ◽  
Autoimmune Response ◽  
Wild Type ◽  
Effector Cells ◽  
Inflammatory Conditions ◽  
Receptor Component ◽  
And Function

AbstractInterleukin-2 (IL-2) controls the homeostasis and function of regulatory T cells (Tregs) and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved Treg-specificity. From a panel of rationally designed IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg-selectivity due to increased dependence on the IL-2-receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared to Fc-fused wild-type IL-2. Preferential Treg enrichment was also observed in the presence of activated pathogenic T cells in the autoimmune target organ, despite a loss of Treg-selectivity in an IL-2R-proximal response. These features allowed for extended resolution of spontaneous autoimmunity using infrequent dosing schedules. Thus, IL-2 muteins enable efficient, flexible, and targeted control of the autoimmune response.One Sentence SummaryA CD25-dependent IL-2 mutein selectively expands regulatory T cells and provides potent and targeted control of autoimmunity.

scholarly journals An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice

2020 ◽  
Vol 5 (50) ◽  
pp. eaba5264 ◽  
Author(s):  
Liliane Khoryati ◽  
Minh Nguyet Pham ◽  
McKenna Sherve ◽  
Swarnima Kumari ◽  
Kevin Cook ◽  
...  
Keyword(s):  
T Cells ◽  
Dose Range ◽  
Interleukin 2 ◽  
Nod Mice ◽  
Effector Cells ◽  
Inflammatory Conditions ◽  
Cell Selectivity ◽  
Receptor Component ◽  
Cell Enrichment ◽  
And Function

Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (Treg) cells, and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2–based therapeutics with improved Treg cell specificity. From a panel of rationally designed murine IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg cell selectivity due to increased dependence on the IL-2 receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg cell enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg cell growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared with Fc-fused wild-type IL-2. Preferential Treg cell enrichment was also observed in the presence of activated pathogenic T cells in the pancreas of nonobese diabetic (NOD) mice, despite a loss of Treg cell selectivity in an IL-2R proximal response. These properties facilitated potent and extended resolution of NOD diabetes with infrequent dosing schedules.

CD101 Expression and Function in Normal and Rheumatoid Arthritis-affected Human T Cells and Monocytes/Macrophages

2010 ◽  
Vol 38 (3) ◽  
pp. 419-428 ◽  
Author(s):  
DRAGAN V. JOVANOVIC ◽  
LAURENCE BOUMSELL ◽  
ARMAND BENSUSSAN ◽  
XAVIER CHEVALIER ◽  
ARTURO MANCINI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Map Kinase ◽  
Surface Expression ◽  
P38 Map Kinase ◽  
Autoimmune Response ◽  
Human Immune System ◽  
Kinase Activation ◽  
And Function

Objective.It was recently reported that CD101 surface expression discriminates potency among CD4+CD25+ FoxP3+ regulatory T cells in the mouse. We investigated whether CD101 may also have a role in the suppressor function of regulatory T cells in humans given that the latter population may affect the autoimmune response in patients with rheumatoid arthritis (RA).Methods.Sorted T cells and monocyte/macrophage cell populations were analyzed by flow cyto metry using conjugated antibodies specific for cell-surface markers. T cell proliferation assays were conducted by [3H]thymidine incorporation and CD8highcytotoxicity measurements by Cyto-Scan-LDH cytotoxicity assays. ELISA were used to measure cytokines in cell culture supernatants and Western blotting was performed for profiling mitogen-activated protein (MAP) kinase activation using specific antiphospholipid antibodies.Results.CD101 expression coincided with PMA-induced monocyte/leukocyte lineage differentiation. CD8highCD101− T cells exhibited greater cytotoxic activity than CD8highCD101+ T cells, while no difference was observed between CD4CD25highCD101+ and CD4CD25highCD101− Treg inhibitory activity through responder T cells. LPS-induced proinflammatory cytokine production and p38 MAP kinase activation were made possible by ligation of CD101 with an anti-CD101 antibody F(ab’)2fragment.Conclusion.These results suggested a modulatory/coregulatory function of CD101 in the human immune system, in contrast to murine models, in which CD101 surface expression discriminates potency among FoxP3+ regulatory T cells. Cytotoxic CD8highCD101+ T cells were markedly less cytotoxic than CD8highT cells negative for the CD101 antigen and were conspicuously downregulated in patients with RA, suggesting a possible role for CD101 expression and function in the control of certain manifestations of RA pathology.

scholarly journals IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2409-2414 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Steven A. Rosenberg
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Selective Inhibition ◽  
High Dose ◽  
Protein Levels ◽  
And Function ◽  
The Impact

Abstract Interleukin-2 (IL-2) is historically known as a T-cell growth factor. Accumulating evidence from knockout mice suggests that IL-2 is crucial for the homeostasis and function of CD4+CD25+ regulatory T cells in vivo. However, the impact of administered IL-2 in an immune intact host has not been studied in rodents or humans. Here, we studied the impact of IL-2 administration on the frequency and function of human CD4+CD25hi T cells in immune intact patients with melanoma or renal cancer. We found that the frequency of CD4+CD25hi T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with regulatory T cells. In addition, both transcript and protein levels of Foxp3, a transcription factor exclusively expressed on regulatory T cells, were consistently increased in CD4 T cells following IL-2 treatment. Functional analysis of the increased number of CD4+CD25hi T cells revealed that this population exhibited potent suppressive activity in vitro. Collectively, our results demonstrate that administration of high-dose IL-2 increased the frequency of circulating CD4+CD25hi Foxp3+ regulatory T cells. Our findings suggest that selective inhibition of IL-2-mediated enhancement of regulatory T cells may improve the therapeutic effectiveness of IL-2 administration. (Blood. 2006;107:2409-2414)

scholarly journals Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions

2016 ◽  
Vol 14 (6) ◽  
pp. 521-528 ◽  
Author(s):  
Jian Gu ◽  
Xuhao Ni ◽  
Xiongxiong Pan ◽  
Hao Lu ◽  
Yunjie Lu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Inflammatory Conditions ◽  
And Function

Wild-type FOXP3 is selectively active in CD4+CD25hi regulatory T cells of healthy female carriers of different FOXP3 mutations

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4138-4141 ◽  
Author(s):  
Sara Di Nunzio ◽  
Massimiliano Cecconi ◽  
Laura Passerini ◽  
Alicia N. McMurchy ◽  
Udo Baron ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Peripheral Blood Lymphocytes ◽  
Random Pattern ◽  
Wild Type ◽  
Allele Distribution ◽  
Healthy Female ◽  
And Function ◽  
Memory Cd4 T Cells ◽  
Female Carriers

Abstract Forkhead box P3 (FOXP3) is constitutively expressed by CD4+CD25hi regulatory T cells (nTregs). Mutations of FOXP3 cause a severe autoimmune syndrome known as immune dysregulation polyendocrinopathy enteropathy X-linked, in which nTregs are absent or dysfunctional. Whether FOXP3 is essential for both differentiation and function of human nTreg cells remains to be demonstrated. Because FOXP3 is an X-linked gene subject to X-chromosome inactivation (XCI), we studied 9 healthy female carriers of FOXP3 mutations to investigate the role of wild-type (WT) versus mutated FOXP3 in different cell subsets. Analysis of active WT versus mutated (mut)–FOXP3 allele distribution revealed a random pattern of XCI in peripheral blood lymphocytes and in naive and memory CD4+T cells, whereas nTregs expressed only the active WT-FOXP3. These data demonstrate that expression of WT-FOXP3 is indispensable for the presence of a normal nTreg compartment and suggest that FOXP3 is not necessary for effector T-cell differentiation in humans.

scholarly journals SOCS1 and Regulation of Regulatory T Cells Plasticity

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Reiko Takahashi ◽  
Akihiko Yoshimura
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Molecular Mechanisms ◽  
Foxp3 Expression ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Cell Integrity ◽  
Inflammatory Conditions ◽  
A Minor ◽  
And Function

Several reports have suggested that natural regulatory T cells (Tregs) lose Forkhead box P3 (Foxp3) expression and suppression activity under certain inflammatory conditions. Treg plasticity has been studied because it may be associated with the pathogenesis of autoimmunity. Some studies showed that a minor uncommitted Foxp3+T cell population, which lacks hypomethylation at Treg-specific demethylation regions (TSDRs), may convert to effector/helper T cells. Suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling, has been reported to play an important role in Treg cell integrity and function by protecting the cells from excessive inflammatory cytokines. In this review, we discuss Treg plasticity and maintenance of suppression functions in both physiological and pathological settings. In addition, we discuss molecular mechanisms of maintaining Treg plasticity by SOCS1 and other molecules. Such information will be useful for therapy of autoimmune diseases and reinforcement of antitumor immunity.

scholarly journals STAT6 Pathway Is Critical for the Induction and Function of Regulatory T Cells Induced by Mucosal B Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Kuan-Hua Chu ◽  
Szu-Yu Lin ◽  
Bor-Luen Chiang
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Cell Generation ◽  
Peyer’S Patch ◽  
Wild Type ◽  
Peyer's Patch ◽  
And Function ◽  
P Cells

B cells could convert naïve T cells into regulatory T cells (so-called Treg-of-B cells) which have the ability to treat animal models of inflammatory diseases, including allergic asthma, collagen-induced arthritis and colitis; however, the mechanisms of Treg-of-B cell generation remain unclear. In this study, we investigated the role of STAT6 in the generation of Treg-of-B (P) cells, which Treg cells were generated by Peyer’s patch B cells (P stands for Peyer’s patch). CD4+CD25- T cells from wild type, STAT6 knockout and IL-4 knockout mice were cocultured with wild type Peyer’s patch B cells for Treg-of-B (P) cell generation. A murine asthmatic model was used to analyze the in vivo regulatory function of Treg-of-B (P) cells. The data demonstrated that STAT6 played a critical role in the generation of Treg-of-B (P) cells, which confirmed with STAT6-deficient T cells and the STAT6 inhibitor AS1517499. When STAT6 was lacking, Treg-of-B (P) cells exerted impaired suppressive ability with decreased LAG3 expression. Furthermore, Peyer’s patch B cells played an essential role in regulatory T cell generation. In the absence of Peyer’s patch B cells, T cells expressed decreased phosphorylated STAT6, which was followed by decreased LAG3 expression and impaired suppressive ability, suggesting that Peyer’s patch B cells provided the critical signal to activate STAT6 phosphorylation in T cells. Moreover, STAT6 deficient Treg-of-B (P) cells could not alleviate inflammation in an animal model of asthma in vivo. IL-4 was downstream of phosphorylated STAT6 and maintained Treg-of-B (P) cell survival with increased expression of Bcl-2 and BclXL. We reported a novel finding that the STAT6-LAG3 signaling axis is important for the induction and function of Treg-of-B (P) cells.

scholarly journals Reduced Numbers and Impaired Function of Regulatory T Cells in Peripheral Blood of Ischemic Stroke Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Johanna Ruhnau ◽  
Juliane Schulze ◽  
Bettina von Sarnowski ◽  
Marie Heinrich ◽  
Sönke Langner ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Peripheral Blood ◽  
Experimental Stroke ◽  
Stroke Patients ◽  
Effector Cells ◽  
T Effector Cells ◽  
Treg Function ◽  
Age Dependent ◽  
And Function

Background and Purpose. Regulatory T cells (Tregs) have been suggested to modulate stroke-induced immune responses. However, analyses of Tregs in patients and in experimental stroke have yielded contradictory findings. We performed the current study to assess the regulation and function of Tregs in peripheral blood of stroke patients. Age dependent expression of CD39 on Tregs was quantified in mice and men. Methods. Total FoxP3+ Tregs and CD39+FoxP3+ Tregs were quantified by flow cytometry in controls and stroke patients on admission and on days 1, 3, 5, and 7 thereafter. Treg function was assessed by quantifying the inhibition of activation-induced expression of CD69 and CD154 on T effector cells (Teffs). Results. Total Tregs accounted for 5.0% of CD4+ T cells in controls and <2.8% in stroke patients on admission. They remained below control values until day 7. CD39+ Tregs were most strongly reduced in stroke patients. On day 3 the Treg-mediated inhibition of CD154 upregulation on CD4+ Teff was impaired in stroke patients. CD39 expression on Treg increased with age in peripheral blood of mice and men. Conclusion. We demonstrate a loss of active FoxP3+CD39+ Tregs from stroke patient’s peripheral blood. The suppressive Treg function of remaining Tregs is impaired after stroke.

scholarly journals Balancing Inflammation: The Link between Th17 and Regulatory T Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Maggie L. Diller ◽  
Ragini R. Kudchadkar ◽  
Keith A. Delman ◽  
David H. Lawson ◽  
Mandy L. Ford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Th17 Cells ◽  
Cell Lineage ◽  
Effector Functions ◽  
Inflammatory Conditions ◽  
Cell Compartments ◽  
Th17 Cell Differentiation ◽  
And Function

CD4+T cell compartments in mouse and man are composed of multiple distinct subsets each possessing unique phenotypic and functional characteristics. IL-17-producing CD4+T cells (Th17 cells) represent a distinct subset of the CD4+T cell lineage. Recent evidence suggests that Th17 cells carry out effector functions similar to cytotoxic CD8+T cells and play an important role in the clearance of extracellular pathogens and fungi. Th17 cell differentiation and function are closely related to the development and function of regulatory T cells(TREG). The balance between these two cell populations is essential for immune homeostasis and dysregulation of this balance has been implicated in a variety of inflammatory conditions including autoimmunity, allograft rejection, and tumorigenesis. Emerging evidence reports a significant amount of plasticity between the Th17 and regulatory T cell compartments, and the mechanisms by which these cells communicate and influence each other are just beginning to be understood. In this review, we highlight recent findings detailing the mechanisms driving Th17 andTREGplasticity and discuss the biologic consequences of their unique relationship.

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