CD4+ T cell heterogeneity in gestational age and preeclampsia using single-cell RNA sequencing

Sayaka Tsuda; Shigeyuki Shichino; Tamara Tilburgs; Tomoko Shima; Keiko Morita; Akemi Yamaki-Ushijima; Krishna Roskin; Michio Tomura; Azusa Sameshima; Shigeru Saito; Akitoshi Nakashima

doi:10.3389/fimmu.2024.1401738

CD4⁺ T cell heterogeneity in gestational age and preeclampsia using single-cell RNA sequencing

Front Immunol. 2024 May 7:15:1401738. doi: 10.3389/fimmu.2024.1401738. eCollection 2024.

Authors

Affiliations

¹ Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.
² Division of Immunobiology, Center for Inflammation and Tolerance, Cincinnati Children's Hospital, Cincinnati, OH, United States.
³ Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute of Biomedical Sciences, Tokyo University of Science, Chiba, Japan.
⁴ Divisions of Biomedical Informatics & Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH, United States.
⁵ Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan.
⁶ Ladies' Clinic We! Toyama, Toyama, Japan.
⁷ University of Toyama, Toyama, Japan.

^# Contributed equally.

Abstract

A balance between pro-inflammatory decidual CD4⁺ T cells and FOXP3⁺ regulatory T cells (FOXP3⁺ Tregs) is important for maintaining fetomaternal tolerance. Using single-cell RNA-sequencing and T cell receptor repertoire analysis, we determined that diversity and clonality of decidual CD4⁺ T cell subsets depend on gestational age. Th1/Th2 intermediate and Th1 subsets of CD4⁺ T cells were clonally expanded in both early and late gestation, whereas FOXP3⁺ Tregs were clonally expanded in late gestation. Th1/Th2 intermediate and FOXP3⁺ Treg subsets showed altered gene expression in preeclampsia (PE) compared to healthy late gestation. The Th1/Th2 intermediate subset exhibited elevated levels of cytotoxicity-related gene expression in PE. Moreover, increased Treg exhaustion was observed in the PE group, and FOXP3⁺ Treg subcluster analysis revealed that the effector Treg like subset drove the Treg exhaustion signatures in PE. The Th1/Th2 intermediate and effector Treg like subsets are possible inflammation-driving subsets in PE.

Keywords: CD4 + T cell; FOXP3; T cell receptor; immune tolerance; preeclampsia; pregnancy; regulatory T cell; single-cell RNA-sequencing.

MeSH terms

Adult
CD4-Positive T-Lymphocytes / immunology
Decidua / immunology
Female
Forkhead Transcription Factors* / genetics
Forkhead Transcription Factors* / metabolism
Gestational Age*
Humans
Pre-Eclampsia* / genetics
Pre-Eclampsia* / immunology
Pregnancy
Sequence Analysis, RNA
Single-Cell Analysis* / methods
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism
T-Lymphocytes, Regulatory* / immunology
Th1 Cells / immunology

Substances

FOXP3 protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by JSPS KAKENHI Grant Numbers 17K11221 (TS), 19K18690 (ST), 21K16764 (ST), 22KK0287(ST), 19K09750(AN), and 22H03223 (AN), AMED under Grant Number JP18gk0110018 (SSa), 42th Japan Medical Women’s Association research grant (ST).