Tff1-expressing Tregs in lung prevent exacerbation of Bleomycin-induced pulmonary fibrosis

Masaaki Okamoto; Ayumi Kuratani; Daisuke Okuzaki; Naganori Kamiyama; Takashi Kobayashi; Miwa Sasai; Masahiro Yamamoto

doi:10.3389/fimmu.2024.1440918

Tff1-expressing Tregs in lung prevent exacerbation of Bleomycin-induced pulmonary fibrosis

Front Immunol. 2024 Sep 2:15:1440918. doi: 10.3389/fimmu.2024.1440918. eCollection 2024.

Authors

Masaaki Okamoto^{1

2}, Ayumi Kuratani^{1

2}, Daisuke Okuzaki³, Naganori Kamiyama⁴, Takashi Kobayashi^{4

5}, Miwa Sasai^{1

2

6}, Masahiro Yamamoto^{1

2

6}

Affiliations

¹ Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
² Laboratory of Immunoparasitology, World Premier International Research Center Initiative Immunology Frontier Research Center, Osaka University, Suita, Japan.
³ Genome Information Research Center, Osaka University, Suita, Japan.
⁴ Department of Infectious Disease Control, Faculty of Medicine, Oita University, Oita, Japan.
⁵ Research Center for GLOBAL and LOCAL Infectious Diseases, Oita University, Oita, Japan.
⁶ Department of Immunoparasitology, Center for Infectious Disease Education and Research, Osaka University, Suita, Japan.

Abstract

Bleomycin (BLM) induces lung injury, leading to inflammation and pulmonary fibrosis. Regulatory T cells (Tregs) maintain self-tolerance and control host immune responses. However, little is known about their involvement in the pathology of pulmonary fibrosis. Here we show that a unique Treg subset expressing trefoil factor family 1 (Tff1) emerges in the BLM-injured lung. These Tff1-expressing Tregs (Tff1-Tregs) were induced by IL-33. Moreover, although Tff1 ablation in Tregs did not change the pathological condition, selective ablation of Tff1-Tregs using an intersectional genetic method promoted pro-inflammatory features of macrophages in the injured lung and exacerbated the fibrosis. Taken together, our study revealed the presence of a unique Treg subset expressing Tff1 in BLM-injured lungs and their critical role in the injured lung to ameliorate fibrosis.

Keywords: Bleomycin; Tff1; Treg; VeDTR; fibrosis.

MeSH terms

Animals
Bleomycin* / adverse effects
Disease Models, Animal
Interleukin-33 / genetics
Interleukin-33 / metabolism
Lung* / immunology
Lung* / metabolism
Lung* / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Pulmonary Fibrosis* / chemically induced
Pulmonary Fibrosis* / metabolism
T-Lymphocytes, Regulatory* / immunology
T-Lymphocytes, Regulatory* / metabolism
Trefoil Factor-1* / genetics
Trefoil Factor-1* / metabolism

Substances

Bleomycin
Trefoil Factor-1
Interleukin-33

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by Japan Science and Technology Agency (JPMJFR206D and JPMJMS2025); Agency for Medical Research and Development (JP20fk0108137, JP23fk0108682, and JP223fa627002); Ministry of Education, Culture, Sports, Science and Technology (24K10257); the program from Joint Usage and Joint Research Programs of the Institute of Advanced Medical Sciences, Tokushima University; Takeda Science Foundation; Mochida Memorial Foundation; Astellas Foundation for Research on Metabolic Disorders; Naito Foundation; the Chemo-Sero-Therapeutic Research Institute; Research Foundation for Microbial Diseases of Osaka University; BIKEN Taniguchi Scholarship; The Nippon Foundation - Osaka University Project for Infectious Disease Prevention; Joint Research Program of Research Center for Global and Local Infectious Diseases of Oita University (2021B06); the Research Fellow of Scholarship for Doctoral Students in Immunology.