Blockade of CTLA-4 and Tim-3 pathways induces fetal loss with altered cytokine profiles by decidual CD4 + T cells

Songcun Wang, Chunqin Chen, Mengdie Li, Jinfeng Qian, Fengyun Sun, Yunyun Li, Min Yu, Mingyan Wang, Xingxing Zang, Rui Zhu, Dajin Li, Meirong Du

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The single and/or combination use of immune checkpoint blockade therapies in human infectious diseases and cancer are rapidly expanding. Despite early efforts, substantial uncertainty remains about the safety and efficacy of immune checkpoint blockade in some populations. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and T-cell immunoglobulin mucin-3 (Tim-3) are the major targetable co-inhibitory receptors on T cells. Here we showed that in animal studies, treatment with either CTLA-4- or Tim-3-blocking antibody caused greater susceptibility to fetal loss with altered cytokine profiles by decidual CD4 + T (dCD4 + T) cells. CTLA-4 and Tim-3 pathways appeared to play key roles in maintaining maternal-fetal tolerance by regulating the function of dCD4 + T cells. In addition, the abnormality in number and functionality of dCTLA-4 + Tim-3 + CD4 + T cells was associated with miscarriage. These findings underscored the important roles of the CTLA-4 and Tim-3 pathways in regulating dCD4 + T cells function and maintaining normal pregnancy. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care.

Original languageEnglish (US)
Article number15
JournalCell Death and Disease
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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