Three Types of Functional Regulatory T Cells Control T Cell Responses at the Human Maternal-Fetal Interface

Maria Salvany-Celades; Anita van der Zwan; Marilen Benner; Vita Setrajcic-Dragos; Hannah Ananda Bougleux Gomes; Vidya Iyer; Errol R Norwitz; Jack L Strominger; Tamara Tilburgs

doi:10.1016/j.celrep.2019.04.109

Three Types of Functional Regulatory T Cells Control T Cell Responses at the Human Maternal-Fetal Interface

Cell Rep. 2019 May 28;27(9):2537-2547.e5. doi: 10.1016/j.celrep.2019.04.109.

Authors

Maria Salvany-Celades¹, Anita van der Zwan², Marilen Benner¹, Vita Setrajcic-Dragos¹, Hannah Ananda Bougleux Gomes¹, Vidya Iyer³, Errol R Norwitz³, Jack L Strominger¹, Tamara Tilburgs⁴

Affiliations

¹ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02130, USA.
² Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02130, USA; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
³ Department of Obstetrics & Gynecology, Tufts Medical Center, Boston, MA 02111, USA; Mother Infant Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
⁴ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02130, USA. Electronic address: tilburgs@fas.harvard.edu.

PMID: 31141680
DOI: 10.1016/j.celrep.2019.04.109

Abstract

During pregnancy, maternal regulatory T cells (Tregs) are important in establishing immune tolerance to invading fetal extravillous trophoblasts (EVTs). CD25^HIFOXP3+ Tregs are found at high levels in decidual tissues and have been shown to suppress fetus-specific and nonspecific responses. However, limited data are available on additional decidual Treg types and the mechanisms by which they are induced. This study investigated three distinct decidual CD4+ Treg types in healthy pregnancies with a regulatory phenotype and the ability to suppress T cell responses: CD25^HIFOXP3+, PD1^HIIL-10+, and TIGIT+FOXP3^dim. Moreover, co-culture of HLA-G+ EVTs or decidual macrophages with blood CD4+ T cells directly increased the proportions of CD25^HIFOXP3+ Tregs compared to T cells cultured alone. EVTs also increased PD1^HI Tregs that could be inhibited by HLA-C and CD3 antibodies, suggesting an antigen-specific induction. The presence of distinct Treg types may allow for the modulation of a variety of inflammatory responses in the placenta.

Keywords: FOXP3; HLA-C; HLA-G; IL-10; Trl cell; decidua; immune tolerance; placenta; pregnancy; trophoblast.

Publication types

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

MeSH terms

CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
Cells, Cultured
Decidua / immunology*
Decidua / metabolism
Female
Fetus / immunology*
Forkhead Transcription Factors / metabolism
HLA-C Antigens / immunology*
Humans
Immune Tolerance / immunology*
Interleukin-10 / immunology
Interleukin-10 / metabolism
Placenta / immunology
Placenta / metabolism
Pregnancy
Programmed Cell Death 1 Receptor / metabolism
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism
Trophoblasts / immunology
Trophoblasts / metabolism

Substances

FOXP3 protein, human
Forkhead Transcription Factors
HLA-C Antigens
IL10 protein, human
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Interleukin-10