CCR8+ decidual regulatory T cells maintain maternal-fetal immune tolerance during early pregnancy

Zhuqing Li; Pinxin Si; Tingting Meng; Xiaoran Zhao; Chendi Zhu; Dunfang Zhang; Shutong Meng; Nianyu Li; Ran Liu; Tianxiang Ni; Junhao Yan; Hongchang Li; Ning Zhao; Chao Zhong; Yingying Qin; WanJun Chen; Zi-Jiang Chen; Xue Jiao

doi:10.1126/sciimmunol.ado2463

CCR8⁺ decidual regulatory T cells maintain maternal-fetal immune tolerance during early pregnancy

Sci Immunol. 2025 Apr 18;10(106):eado2463. doi: 10.1126/sciimmunol.ado2463. Epub 2025 Apr 18.

Authors

Zhuqing Li^{1

2

3

4

5

6

7

8}, Pinxin Si^{1

2

3

4

5

6

7}, Tingting Meng^{1

2

3

4

5

6

7}, Xiaoran Zhao^{1

2

3

4

5

6

7}, Chendi Zhu^{1

2

3

4

5

6

7}, Dunfang Zhang⁹, Shutong Meng^{1

2

3

4

5

6

7}, Nianyu Li^{1

2

3

4

5

6

7}, Ran Liu^{1

2

3

4

5

6

7}, Tianxiang Ni^{1

2

3

4

5

6

7}, Junhao Yan^{1

2

3

4

5

6

7}, Hongchang Li^{1

2

3

4

5

6

7}, Ning Zhao¹⁰, Chao Zhong¹¹, Yingying Qin^{1

2

3

4

5

6

7

8}, WanJun Chen¹², Zi-Jiang Chen^{1

2

3

4

5

6

7

13

14}, Xue Jiao^{1

2

3

4

5

6

7}

Affiliations

¹ State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Second Hospital, Shandong University, Jinan, Shandong 250012, China.
² National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China.
³ Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China.
⁴ Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong 250012, China.
⁵ Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong 250012, China.
⁶ Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong 250012, China.
⁷ Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China.
⁸ Department of Reproductive Medicine, Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
⁹ Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
¹⁰ Analytical Biosciences Limited, Beijing 100191, China.
¹¹ Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, Peking University, Beijing 100191, China.
¹² Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
¹³ Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China.
¹⁴ Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

PMID: 40249828
DOI: 10.1126/sciimmunol.ado2463

Abstract

Regulatory T (T_reg) cells play a vital role in maintaining maternal immune tolerance to the semiallogeneic fetus during pregnancy. T_reg cell population heterogeneity and tissue-specific functions in the human decidua remain largely unknown. Here, using single-cell transcriptomic and T cell receptor sequencing of human CD4⁺ T cells from first-trimester deciduae and matched peripheral blood of pregnant women, we identified a highly activated, immunosuppressive CCR8⁺ T_reg cell subset specifically enriched in the decidua (dT_reg cells). CCR8⁺ dT_reg cells were decreased in patients with recurrent pregnancy loss (RPL) and an abortion-prone mouse model. Depletion of CCR8⁺ dT_reg cells increased susceptibility to fetal loss, with altered decidual immune profiles. Adoptive transfer of CCR8⁺ T_reg cells rescued fetal loss in abortion-prone mice. The CCR8 ligand CCL1 was mainly produced by decidual CD49a⁺ natural killer cells and was significantly decreased in patients with RPL. Our data demonstrate that CCR8⁺ dT_reg cells are required to maintain maternal-fetal tolerance and highlight potential avenues for RPL therapies.

MeSH terms

Abortion, Habitual / immunology
Adult
Animals
Decidua* / immunology
Female
Humans
Immune Tolerance* / immunology
Mice
Mice, Inbred C57BL
Pregnancy
Receptors, CCR8* / immunology
Receptors, CCR8* / metabolism
T-Lymphocytes, Regulatory* / immunology

Substances

Receptors, CCR8