Induced Regulatory T Cells Superimpose Their Suppressive Capacity with Effector T Cells in Lymph Nodes via Antigen-Specific S1p1-Dependent Egress Blockage.

Shuang Geng,Xiaoping Xie,Yechun Pei,Xiaoyu Zhou,Gan Zhao,Yiwei Zhong,Bin Wang,Yan Shi,Huiyuan Zhang,Hu Liu

doi:10.3389/fimmu.2017.00663

Abstract

Regulatory T cells (Tregs) restrict overexuberant lymphocyte activation. While close proximity between Tregs and their suppression targets is important for optimal inhibition, and literature indicates that draining lymph nodes (LNs) may serve as a prime location for the suppression, signaling details orchestrating this event are not fully characterized. Using a protocol to enable peripheral generation of inducible antigen-specific Tregs (asTregs) to control allergen-induced asthma, we have identified an antigen-specific mechanism that locks asTregs within hilar LNs which in turn suppresses airway inflammation. The suppressive asTregs, upon antigen stimulation in the LN, downregulate sphingosine-1-phosphate receptor 1 egress receptor expression. These asTregs in turn mediate the downregulation of the same receptor on incoming effector T cells. Therefore, asTregs and effector T cells are locked in these draining LNs for prolonged interactions. Disruption of individual steps of this retention sequence abolishes the inflammation controlled by asTregs. Collectively, this study identifies a new requirement of spatial congregation with their suppression targets essential for asTreg functions and suggests therapeutic programs via Treg traffic control.

Highlights

Regulatory T cells (Tregs) play a crucial role in balancing the activation state of the immune system [1, 2]
We previously demonstrated that coimmunization with antigen plus its cognate coding DNA construct induced a set of CD4+CD25−Foxp3+CTLA-4lowPD1lowGITRhi Tregs, designated as antigen-specific Treg here
We previously developed a vaccine based on coimmunization of OVA peptide with a DNA construct carrying the same epitope coding sequence

Summary

INTRODUCTION

Regulatory T cells (Tregs) play a crucial role in balancing the activation state of the immune system [1, 2]. Antigen-Induced Cohabitation of asTreg and Teff in LN these Tregs is limited to a niche percentage set by other TCR specificities [9]. This by design leaves a gap in immune suppression to be filled by pTregs risen in response to environmental factors. In experimental settings, signaling via TCR coupled to anti-inflammatory cytokines, TGF-β and IL-10, typically leads to the generation of canonical pTregs that share Foxp and CD25 expression with tTregs, mostly but not exclusively characterized by the lack of Helios and neuropilin 1 [14, 15]. This work reveals a spatiotemporal regulation of Tregs essential for their suppressive capacity

RESULTS

DISCUSSION

MATERIALS AND METHODS

ETHICS STATEMENT