Dataset Information

S1P₁ deletion differentially affects TH17 and Regulatory T cells.

ABSTRACT: Sphingosine-1 phosphate receptor 1 (S1P₁) is critical for the egress of T and B cells out of lymphoid organs. Although S1P₁ agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P₁ signaling regulates Th17 and T_reg cell homeostasis. To study the impact of S1P₁ signaling on Th17 and T_reg cell biology, we specifically deleted S1P₁ in Th17 and T_reg cells using IL-17A ^Cre and Foxp3 ^Cre mice, respectively. Deletion of S1P₁ in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE). On the other hand, permanent deletion of S1P₁ in T_reg cells resulted in autoimmunity and acute deletion rendered mice more susceptible to EAE. Importantly, our study revealed that S1P₁ not only regulated the egress of T_reg cells out of lymphoid organs and subsequent non-lymphoid tissue distribution but also their phenotypic diversity. Most of the T_reg cells found in S1P₁-deficient mice as well as MS patients on fingolimod therapy had an activated phenotype and were more prone to apoptosis, thus converted to effector T_reg. Our results provide novel insight into the functions of S1P₁ and potential impact of long term fingolimod use on Th17 and T_reg cell biology and general health in MS patients.

SUBMITTER: Eken A

PROVIDER: S-EPMC5635040 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

S1P1 deletion differentially affects TH17 and Regulatory T cells.

Eken Ahmet A Duhen Rebekka R Singh Akhilesh K AK Fry Mallory M Buckner Jane H JH Kita Mariko M Bettelli Estelle E Oukka Mohamed M

Scientific reports 20171010 1

Sphingosine-1 phosphate receptor 1 (S1P1) is critical for the egress of T and B cells out of lymphoid organs. Although S1P1 agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P1 signaling regulates Th17 and Treg cell homeostasis. To study the impact of S1P1 signaling on Th17 and Treg cell biology, we specifically deleted S1P1 in Th17 and Treg cells using IL ...[more]

PMID: 29018225

Similar Datasets

Project description:AimVisceral obesity is a key risk factor in the development of oesophagogastric junctional adenocarcinoma (OGJ), predominantly via generation of systemic low grade inflammation. Obesity-induced inflammation promotes resistance to current standards of care, enhancing tumour cell growth and survival. This study investigates the effect of the visceral adipose tissue secretome from OGJ patients with early versus advanced tumours on T-cell immunity and the role of immune checkpoint blockade in enhancing anti-tumour immunity.Methods and resultsVisceral adipose conditioned media (ACM) from both early and late-stage OGJ patients significantly altered T cell activation status, upregulating co-stimulatory marker CD27 on T cells. ACM from both early and late-stage OGJ patients significantly altered immune checkpoint expression profiles downregulating immune checkpoints (ICs) on the surface of dual Th1/17-like and Th17-like cells and upregulating ICs on the surface of Th1-like cells and Treg cells. ACM derived from early-stage OGJ patients but not late-stage OGJ patients increased IFN-γ production by T cells. The addition of immune checkpoint blockers (ICBs) did not increase IFN-γ production by T cells in the presence of late-stage ACM, collectively highlighting the dichotomous immunostimulatory effect of early-stage ACM and immune-inhibitory effect of late-stage ACM. Interestingly, ACM from early-stage OGJ patients was more pro-inflammatory than ACM from late-stage patients, reflected by decreased levels of IL-17A/F, TNF-α, IL-1RA and IL-5.ConclusionThe ACM-induced upregulation of ICs on T cells highlights a therapeutic vulnerability that could be exploited by ICBs to harness anti-cancer immunity and improve clinical outcomes for OGJ patients. Schematic workflow - (A) visceral adipose tissue was taken from OAC patients at time of surgery and cultured for 72 h in media. (B) The harvested ACM was co-cultured with healthy donor PBMCs that were concurrently activated with anti-CD3/28 for 48 h and T cell immunophenotyping was carried out by flow cytometry. Key findings - (A) Early and late stage ACM enhanced a Th1-like phenotype and upregulated CTLA-4 on Th1-like cells. A Th17-like phenotype was also enhanced in addition with a Treg-like phenotype. CTLA-4 and PD-L1 were upregulated on the surface of Treg-like cells. (B) ICB-attenuated IL-17 production by T cells. However, ACM attenuated ICB-mediated reduction in IL-10 production by T cells. Higher levels of pro-inflammatory factors were found in early stage ACM compared with late stage ACM.

Dataset Information

S1P₁ deletion differentially affects TH17 and Regulatory T cells.

Publications

S1P<sub>1</sub> deletion differentially affects TH17 and Regulatory T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets