Olfactory Ecto-mesenchymal Stem Cell-derived Exosomes Ameliorate Murine Sjögren's Syndrome via Suppressing Tfh Cell Response

Ke Rui; Ziwei Shen; Na Peng; Futao Zhao; Yuan Tang; Shiyi Liu; Xinyi Xu; Chang Liu; Ling Wu; Jie Tian; Liwei Lu

doi:10.2478/rir-2022-0035

Olfactory Ecto-mesenchymal Stem Cell-derived Exosomes Ameliorate Murine Sjögren's Syndrome via Suppressing Tfh Cell Response

Rheumatol Immunol Res. 2022 Dec 31;3(4):198-207. doi: 10.2478/rir-2022-0035. eCollection 2022 Dec.

Authors

Ke Rui^{1

2}, Ziwei Shen³, Na Peng⁴, Futao Zhao⁵, Yuan Tang⁶, Shiyi Liu³, Xinyi Xu³, Chang Liu³, Ling Wu⁷, Jie Tian^{1

3}, Liwei Lu^{6

7}

Affiliations

¹ Institute of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang 212003, Jiangsu Province, China.
² Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang 212003, Jiangsu Province, China.
³ Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212003, Jiangsu Province, China.
⁴ Department of Rheumatology, The Second People's Hospital, China Three Gorges University, Yichang 443000, Hubei Province, China.
⁵ Department of Rheumatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China.
⁶ Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong 999077, China.
⁷ Department of Rheumatology, Shenzhen Hospital, The University of Hong Kong, Shenzhen 518048, Guangdong Province, China.

Abstract

Objectives: To investigate the effect of olfactory ecto-mesenchymal stem cell-derived exosomes (OE-MSC-Exos) on T follicular helper (Tfh) cell response and their implication in treating experimental Sjögrens syndrome (ESS).

Methods: C57BL/6 mice were immunized with salivary glands (SG) proteins to induce ESS mouse model. OE-MSC-Exos were added to the Tfh cell polarization condition, and the proportion of Tfh cells was detected by FCM. The PD-L1 of OE-MSCs was silenced with small interfering RNA to extract siPD-L1-OE-MSC-Exos.

Results: We found that transfer of OE-MSC-Exos markedly attenuated disease progression and reduced Tfh cell response in mice with ESS. In culture, OE-MSC-Exos potently inhibited the differentiation of Tfh cells from naïve T cells. Moreover, OE-MSC-Exos expressed high level of the ligand for the programmed cell death protein 1 (PD-L1), knocking down PD-L1 expression in OE-MSC-Exos significantly decreased their capacity to suppress Tfh cell differentiation in vitro. Consistently, transfer of OE-MSC-Exos with PD-L1 knockdown exhibited profoundly diminished therapeutic effect in ESS mice, accompanied with sustained Tfh cell response and high levels of autoantibody production.

Conclusion: Our results suggest that OE-MSC-Exos may exert their therapeutic effect in ameliorating ESS progression via suppressing Tfh cell response in a PD-L1-dependent manner.

Keywords: PD-L1, Sjögren’s syndrome; Tfh cells; exosomes; mesenchymal stem cells.

Grants and funding

This work was supported by Shenzhen Science and Technology Program (YCYJ20210324114602008), Chongqing International Institute for Immunology (2020YJC10), and National Natural Science Foundation of China (Nos. 81971542, 82171771, 82071817, and 82271854).