Abstract
Decidual CD8+ (dCD8) T cells have been proposed to play important roles in immune protection against the invading pathogens and in tolerance toward the growing semi-allogeneic fetus during early pregnancy. However, their phenotypic and functional characteristics remain poorly defined. Here, we performed the first analysis of the transcriptional and alternative splicing (AS) signatures for human first-trimester dCD8 T cells using high-throughput mRNA sequencing. Our data revealed that dCD8 T cells have distinct transcriptional and AS landscapes when compared with their autologous peripheral blood CD8+ (pCD8) T counterparts. Furthermore, human dCD8 T cells were observed to contain CD8-Treg and effector-memory T-cell subsets, and display enhanced functionality in terms of degranulation and cytokine production on a per-cell basis. Additionally, we have identified the novel splice junctions that use a high ratio of the non-canonical splicing motif GC-AG and found that AS is not a major contributor to the gene expression-level changes between paired pCD8 and dCD8 T cells. Together, our findings not only provide a comprehensive framework of the transcriptional and AS landscapes but also reveal the functional feature of human dCD8 T cells, which are of great importance in understanding the biology of these cells and the physiology of human healthy pregnancy.
Highlights
How the semi-allogeneic fetus can survive and grow within the maternal body but without immune rejection has been a longstanding puzzle for reproductive biologists and immunologists [1]
CD8+ T cells, based on the phenotype of CD3+CD8+CD4−, in paired decidual and peripheral blood samples from three healthy women at the first trimester of normal pregnancy. (B) Summary of mRNA sequencing data of the isolated human peripheral blood CD8+ (pCD8) and autologous decidual CD8+ (dCD8) T cells. 2 × 125-bp paired-end cDNA fragments were acquired after sequencing the polyadenylated [poly(A)+] enriched mRNAs on an Illumina Hiseq 2500 platform, and the sequenced reads was aligned to human reference genome by STAR software. (C) The number and proportion of differentially expressed genes (DEGs) that were upregulated or downregulated in human dCD8 versus pCD8 T cells (P < 0.05, paired test). (D) Heatmap analysis of DEGs using R
Our data showed that human dCD8 T cells highly upregulated the genes related to immune effector process, M phase of mitotic cell cycle, antigen processing and presentation, T-cell activation, and cell proliferation/division (Figures 2 and 4; Figures S3 and S4 in Supplementary Material), indicating that these cells are endowed with elevated activation, highproliferation potential, and enhanced immune response
Summary
How the semi-allogeneic fetus can survive and grow within the maternal body but without immune rejection has been a longstanding puzzle for reproductive biologists and immunologists [1]. The immune cells that populate the decidua are believed to make an important contribution to the maintenance of successful pregnancies, and an improved understanding of the composition, phenotype and function of these cells will provide novel insights into the physiology of normal pregnancy, and the pathogenesis of pregnancy-related complications and poor postnatal health [1,2,3]. Previous studies have shown that decidual CD8+ (dCD8) T cells play important roles in promoting embryo implantation and trophoblast invasion, maintaining maternal tolerance toward the growing semi-allogeneic fetus, as well as in providing immune protections for both mother and fetus against the invading pathogens, during a successful early pregnancy [6,7,8]. A deep understanding of the phenotype and functionality of human dCD8 T cells will help in better characterization of their roles during healthy pregnancies
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