A genetic method specifically delineates Th1-type Treg cells and their roles in tumor immunity

Masaaki Okamoto; Miwa Sasai; Ayumi Kuratani; Daisuke Okuzaki; Masaya Arai; James B Wing; Shimon Sakaguchi; Masahiro Yamamoto

doi:10.1016/j.celrep.2023.112813

A genetic method specifically delineates Th1-type Treg cells and their roles in tumor immunity

Cell Rep. 2023 Jul 25;42(7):112813. doi: 10.1016/j.celrep.2023.112813. Epub 2023 Jul 12.

Authors

Masaaki Okamoto¹, Miwa Sasai², Ayumi Kuratani¹, Daisuke Okuzaki³, Masaya Arai⁴, James B Wing⁵, Shimon Sakaguchi⁴, Masahiro Yamamoto⁶

Affiliations

¹ Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
² Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Department of Immunoparasitology, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka 565-0871, Japan.
³ Genome Information Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
⁴ Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
⁵ Laboratory of Human Immunology (Single Cell Immunology), WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Human Immunology Team, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka 565-0871, Japan.
⁶ Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Department of Immunoparasitology, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka 565-0871, Japan. Electronic address: myamamoto@biken.osaka-u.ac.jp.

PMID: 37440410
DOI: 10.1016/j.celrep.2023.112813

Abstract

Regulatory T (Treg) cells expressing the transcription factor (TF) Foxp3 also express other TFs shared by T helper (Th) subsets under certain conditions. Here, to determine the roles of T-bet-expressing Treg cells, we generate a mouse strain, called VeDTR, in which T-bet/Foxp3 double-positive cells are engineered to be specifically labeled and depleted by a combination of Cre- and Flp-recombinase-dependent gene expression control. Characterization of T-bet⁺Foxp3⁺ cells using VeDTR mice reveals high resistance under oxidative stress, which is involved in accumulation of T-bet⁺Foxp3⁺ cells in tumor tissues. Moreover, short-term depletion of T-bet⁺Foxp3⁺ cells leads to anti-tumor immunity but not autoimmunity, whereas that of whole Treg cells does both. Although ablation of T-bet⁺Foxp3⁺ cells during Toxoplasma infection slightly enhances Th1 immune responses, it does not affect the course of the infection. Collectively, the intersectional genetic method reveals the specific roles of T-bet⁺Foxp3⁺ cells in suppressing tumor immunity.

Keywords: CP: Immunology; Foxp3; T-bet; Th1-Treg cells; VeDTR; intersectional genetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmunity
Forkhead Transcription Factors / metabolism
Mice
T-Box Domain Proteins / metabolism
T-Lymphocytes, Regulatory*
Th1 Cells*

Substances

T-Box Domain Proteins
Forkhead Transcription Factors