A T cell extrinsic mechanism by which IL-2 dampens Th17 differentiation

Anderson, Ana C.; Sullivan, Jenna M.; Tan, Dewar J.; Lee, David H.; Kuchroo, Vijay K.

doi:10.1016/j.jaut.2015.02.001

Cited by 7 publications

(7 citation statements)

References 27 publications

(39 reference statements)

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“…IL-2 has been shown to differentially affect T cell populations within the human CD4 + compartment in vitro: promoting the growth of Th1 cells while negatively impacting Th17 differentiation [21, 23, 30]. In order to more fully investigate the effect of in vivo HDIL-2 on CD4 + T cell effector function we analyzed IFNγ, IL-2, and IL-17 production in 6 patients with advanced stage melanoma on days 0 and 4 of HDIL-2 therapy via flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

“…However, the addition of IL-6 to TGF-β has been shown to downregulate FoxP3 and drive Th17 differentiation, suggesting a reciprocal relationship between regulatory Foxp3 + CD4 + T cells and inflammatory Th17 cells [10, 14]. Studies performed in the setting of IL-2 further support this reciprocity, whereby IL-2 induces expansion of the regulatory T cell compartment and inhibits Th17 cell differentiation [14, 17–21]. However, some studies call into question this dichotomy and have shown that exogenous IL-2 is capable of promoting Th17 expansion, particularly in the setting of autoimmune diseases [22, 23].…”

Section: Introductionmentioning

confidence: 99%

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Exogenous IL-2 Induces FoxP3+ Th17 Cells In Vivo in Melanoma Patients

Diller¹,

Kudchadkar²,

Delman

et al. 2016

Journal of Immunotherapy

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Introduction Th17 cells represent a distinct subset of CD4+ effector T cells with potent pathogenic qualities, capable of directly mediating tumor cell destruction. IL-2 has frequently been shown to have a negative impact on Th17 differentiation while supporting regulatory T cell (FoxP3+CD4+, TREG) growth and development in both in vitro models and in vivo animal models. We investigated the effect of in vivo IL-2 on both the Th17 and FoxP3+CD4+ T cell compartments in a human model of cancer. Methods High-dose IL-2 (HDIL-2) was administered at a dose of 720,000 IU/kg to patients with melanoma (n=7) and peripheral blood was collected at baseline and at 24, 48, 72, and 96 hours post-treatment. PBMCs were isolated and underwent intracellular cytokine and extracellular receptor staining for flow cytometry. Results We report that HDIL-2 increased both frequencies and absolute numbers of Th17 cells on day 4 of treatment. The administration of HDIL-2 to patients with melanoma increased IL-6 production by peripheral immune cells, a cytokine vital in the downregulation of FoxP3 expression and expansion of the Th17 cell population. Furthermore, we demonstrated that FoxP3+CD4+ T cells express IL-17 in patients with melanoma undergoing HDIL-2 therapy. Conclusions Taken together, our findings indicate that HDIL-2 combined with the conditions of malignancy create an immune environment supportive of Th17 differentiation and that expansion of this compartment may occur via the trans-differentiation of IL-17-secreting FoxP3+CD4+ T cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exogenous IL-2 Induces FoxP3+ Th17 Cells In Vivo in Melanoma Patients

Diller¹,

Kudchadkar²,

Delman

et al. 2016

Journal of Immunotherapy

View full text Add to dashboard Cite

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“…IL-2 derived from lung DC cells was recently reported to induce protective Th17 response and restrain fatal hyperinflammation in vivo 37 . IL-2 restrictes in vitro generation of IL-17-Secreting CD4 + T cells via STATA-5, IL-2 and STAT5a/b, which were known to be key regulators of Treg cells, also serve to constrain Th17 polarization 38 . IL-2 can also act T cell intrinsically to dampen differentiation of pathogenic IL-17-producing Th17 cells 38 .…”

Section: Discussionmentioning

confidence: 99%

“…IL-2 restrictes in vitro generation of IL-17-Secreting CD4 + T cells via STATA-5, IL-2 and STAT5a/b, which were known to be key regulators of Treg cells, also serve to constrain Th17 polarization 38 . IL-2 can also act T cell intrinsically to dampen differentiation of pathogenic IL-17-producing Th17 cells 38 . It has been reported that tissue resident macrophage IL-2 drives IFN-γ and IL-27 production in CD11b + APC to dampen pathogenic Th17 differentiation 39 , 40 .…”

Section: Discussionmentioning

confidence: 99%

Clinical and Immunological Effects of rhIL-2 Therapy in Eastern Chinese Patients with Multidrug-resistant Tuberculosis

Tan¹,

Min²,

Dai³

et al. 2017

Sci Rep

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It is urgent to find an optimised therapy regimen for the control of MDR-TB globally. This study aimed to evaluate the efficiacy and safety of a combined regimen of rhIL-2 injection and standard chemotherapy within 18-month duration in a randomized controlled trial conducted in 14 centres in eastern China. From Jan. 2009 to July. 2016, 271 MDR-TB cases were enrolled and followed up in two groups, 142 cases in study group while 129 cases in control group. Clinical efficacy, safety and immune activity (Th1, Th17, Treg, IFN-γ, IL-17) among the two groups were evaluated and compared. After 24-month following up, cure rate in IL-2 group show higher than that in control group (56% VS 36%, P < 0.01). Rate of mycobacterium clearance (sputum negative) within 3 months was significantly higher in IL-2 group (74% VS 59%, P < 0.05) with no adverse events raised. Patients after rhIL-2 treatment showed increasing of Th1 populations and decreasing of Th17 and Regulatory T cells (Treg) populations, while levels of IL-17A, ROR-γt, and Foxp3 mRNA decreased and level of IFN-γ mRNA increased in PBMCs. Thus, rhIL-2 combined regimen within shorter duration achieved high conversion and success rates and improved Th1/Th17 immune responses, with no safety concerns emerging in MDR-TB patients.

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“…This seemingly paradoxical observation is explained by the findings that excess IL-2 in NOD. Idd3 mice increases the function of IL-2-dependent FoxP3 + regulatory T cells, which suppress pancreatic inflammation ( 63 ), and that IL-2 responsive macrophages can suppress inflammatory Th17 responses ( 64 ). IL-21 is also encoded in the Idd3 locus ( 65 ), and NOD.…”

Section: Nod Mice As a Model For Autoimmune Diseasementioning

confidence: 99%

The Non-Obese Diabetic Mouse Strain as a Model to Study CD8+ T Cell Function in Relapsing and Progressive Multiple Sclerosis

et al. 2015

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Multiple sclerosis (MS) is a neurodegenerative disease resulting from an autoimmune attack on central nervous system (CNS) myelin. Although CD4+ T cell function in MS pathology has been extensively studied, there is also strong evidence that CD8+ T lymphocytes play a key role. Intriguingly, CD8+ T cells accumulate in great numbers in the CNS in progressive MS, a form of the disease that is refractory to current disease-modifying therapies that target the CD4+ T cell response. Here, we discuss the function of CD8+ T cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. In particular, we describe EAE in non-obese diabetic (NOD) background mice, which develop a pattern of disease characterized by multiple attacks and remissions followed by a progressively worsening phase. This is highly reminiscent of the pattern of disease observed in nearly half of MS patients. Particular attention is paid to a newly described transgenic mouse strain (1C6) on the NOD background whose CD4+ and CD8+ T cells are directed against the encephalitogenic peptide MOG[35–55]. Use of this model will give us a more complete picture of the role(s) played by distinct T cell subsets in CNS autoimmunity.

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A T cell extrinsic mechanism by which IL-2 dampens Th17 differentiation

Cited by 7 publications

References 27 publications

Exogenous IL-2 Induces FoxP3+ Th17 Cells In Vivo in Melanoma Patients

Exogenous IL-2 Induces FoxP3+ Th17 Cells In Vivo in Melanoma Patients

Clinical and Immunological Effects of rhIL-2 Therapy in Eastern Chinese Patients with Multidrug-resistant Tuberculosis

The Non-Obese Diabetic Mouse Strain as a Model to Study CD8+ T Cell Function in Relapsing and Progressive Multiple Sclerosis

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