Abstract
Decidual CD4+ T (dCD4 T) cells are crucial for the maternal-fetal immune tolerance required for a healthy pregnancy outcome. However, their molecular and functional characteristics are not well elucidated. In this study, we performed the first analysis of transcriptional and alternative splicing (AS) landscapes for paired decidual and peripheral blood CD4+ T (pCD4 T) cells in human early pregnancy using high throughput mRNA sequencing. Our data showed that dCD4 T cells are endowed with a unique transcriptional signature when compared to pCD4 T cells: dCD4 T cells upregulate 1,695 genes enriched in immune system process whereas downregulate 1,011 genes mainly related to mRNA catabolic process and the ribosome. Moreover, dCD4 T cells were observed to be at M phase, and show increased activation, proliferation, and cytokine production, as well as display an effector-memory phenotype and a heterogenous nature containing Th1, Th17, and Treg cell subsets. However, dCD4 T cells undergo a comparable number of upregulated and downregulated AS events, both of which are enriched in the genes related to cellular metabolic process. And the changes at the AS event level do not reflect measurable differences at the gene expression level in dCD4 T cells. Collectively, our findings provide a comprehensive portrait of the unique transcriptional signature and AS profile of CD4+ T cells in human decidua and help us gain more understanding of the functional characteristic of these cells during early pregnancy.
Highlights
The maternal-fetal interface (MFI) is regarded as the interface between the extraembryonic tissues of developing conceptus and the uterine mucosa, and the immune cells at the MFI are the maternal immune cells that populate the decidua [1,2,3]
We found that the gene sets related to the following categories: M phase of mitotic cell cycle, mitotic sister chromatin segregation, M phase (Figure 4A; Figure S6A in Supplementary Material); lymphocyte activation, T cell activation, regulation of lymphocyte activation (Figure 4B; Figure S6B in Supplementary Material); cell proliferation, regulation of cell proliferation (Figure 4C; Figure S6C in Supplementary Material); and cytokine production, cytokine secretion and cytokine biosynthetic process (Figure 4D; Figure S6D in Supplementary Material), were remarkably and positively enriched in dCD4 versus peripheral blood CD4+ T (pCD4 T) cells, indicating that human decidual CD4+ T (dCD4 T) cells stay in M phase, and show increased activation and proliferation, as well as have an enhanced functionality represented by cytokines production
Zhou et al revealed that presentation of captured peptide-MHCII ligands by CD4+ T cells has a stimulatory effect on naive T cells, and these cells with acquired peptide-MHC-II molecules become effector CD4+ T cells that manifest a better recall response [56]
Summary
The maternal-fetal interface (MFI) is regarded as the interface between the extraembryonic tissues of developing conceptus and the uterine mucosa, and the immune cells at the MFI are the maternal immune cells that populate the decidua [1,2,3]. During the first trimester of healthy pregnancy, natural killer (NK) cells, macrophages, and T cells are the most abundant leukocytes in human decidua, whereas dendritic cells (DCs), B cells and NKT cells are rare [3]. Since these decidual leukocytes are reported to play a key role in facilitating tolerance to the semiallogeneic fetus and maintaining a successful pregnancy, a deeper understanding of the molecular and functional features of these cells will provide novel insights into the pathogenesis of pregnancy-related complications and poor postnatal health [3,4,5]. The complexity of dCD4 T cells has not been well elucidated, and a thorough understanding of the molecular and functional features of these cells would shed light on their eventual roles during early pregnancy
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