Toggle Main Menu Toggle Search

Open Access padlockePrints

STING Negatively Regulates Allogeneic T-Cell Responses by Constraining Antigen-Presenting Cell Function

Lookup NU author(s): Dr Lei Huang, Emeritus Professor Andrew Mellor

Downloads


Licence

This is the authors' accepted manuscript of an article that has been published in its final definitive form by Springer Nature, 2021.

For re-use rights please refer to the publisher's terms and conditions.


Abstract

Stimulator of interferon genes (STING)-mediated innate immune activation plays a key role in tumor- and self-DNA elicited anti-tumor immunity and autoimmunity, respectively, yet the mechanism remains largely unclear. We utilized murine models of allogeneic hematopoietic cell transplantation (allo-HCT) to study the biology of STING in antigen-presenting cells (APCs) and T cells. STING expression in donor T cells was dispensable for their ability to induce graft-versus-host disease (GVHD), a major complication of allo-HCT in the clinic. However, when STING-deficient mice were used as recipients, more severe GVHD was induced after allo-HCT. Using bone marrow (BM) chimeras where STING was absent in different compartments, we found that STING-deficiency on host hematopoietic cells was primarily responsible for exacerbating the disease. Furthermore, STING on host CD11c+ cells played a dominant role in the regulation of allogeneic T-cell responses. Mechanistically, STING deficiency resulted in increased survival, activation and function of APCs, including macrophages and dendritic cells (DCs). Consistently, constitutive activation of STING attenuated the survival, activation and function of APCs isolated from STING V154M knock-in mice. In addition, STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression and migration into intestinal tissues, resulting in accelerated/exacerbated GVHD. Using pharmacologic approaches, we demonstrate that systemic administration of a STING agonist (c-di-GMP) to recipient mice before transplantation significantly reduced GVHD mortality. In conclusion, we reveal a novel role of STING in APC activity that dictates T-cell allogeneic responses and validate STING as a potential therapeutic target for controlling GVHD after allo-HCT.


Publication metadata

Author(s): Wu Y, Tang C, Mealer C, Bastian B, Sofi M, Tian L, Schutt S, Choi H, Ticer T, Zhang M, Huang L, Mellor AL, Hu C, Yu X

Publication type: Article

Publication status: Published

Journal: Cellular & Molecular Immunology

Year: 2021

Volume: 18

Pages: 632–643

Online publication date: 26/01/2021

Acceptance date: 25/11/2020

Date deposited: 21/12/2020

ISSN (print): 1672-7681

ISSN (electronic): 2042-0226

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41423-020-00611-6

DOI: 10.1038/s41423-020-00611-6


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share