During early pregnancy, tolerance of the semi-allogeneic fetus necessitates comprehensive modifications of the maternal immune system. How decidual CD8⁺T (CD8⁺dT) cells balance maternal tolerance of the fetus with defense from invading pathogens remains undefined.

We investigated the distribution patterns of CD8⁺T cells and their heterogeneity in paired peripheral blood and decidual tissue in the first trimester of pregnancy using flow cytometry and mRNA-Seq. Gene Set Enrichment Analysis was utilized to determine the transcriptional features of CD8⁺dT cells. Moreover, we examined activation of T cells when they were cocultured with trophoblasts, in addition to the effect of the fetal–maternal environment on peripheral CD8⁺T (CD8⁺pT) cells.

We found that, compared with CD8⁺pT cells, CD8⁺dT cells consisted mainly of effector memory cells (T_EM) and terminally differentiated effector memory cells (T_EMRA). Both T_EM and T_EMRA subsets contained increased numbers of CD27⁺CD28⁻ cells, which have been shown to possess only partial effector functions. In-depth analysis of the gene-expression profiles of CD8⁺dT cells revealed significant enrichment in T cell exhaustion-related genes and core tissue residency signature genes that have been found recently to be shared by tissue resident memory cells and tumor⁻infiltrating lymphocytes (TILs). In accordance with gene expression, protein levels of the exhaustion-related molecules PD-1 and CD39 and the tissue resident molecules CD103 and CXCR3 were increased significantly with almost no perforin secretion in CD8⁺dT cells compared with CD8⁺pT cells. However, the levels of granzyme B, IFN-γ, and IL-4 in CD8⁺dT cells were increased significantly compared with those in CD8⁺pT cells. Both CD8⁺dT and CD8⁺pT cells were not activated after being cocultured with autologous trophoblast cells. Moreover, the production of granzyme B in CD103⁺CD8⁺dT cells decreased significantly compared with that in their CD103⁻ counterparts. Coculture with decidual stromal cells and trophoblasts upregulated CD103 expression significantly in CD8⁺pT cells.

Our findings indicate that the selective silencing of effector functions of resident CD8⁺dT cells may favor maternal–fetal tolerance and that the decidual microenvironment plays an important role in promoting the residency of CD8⁺T cells and their tolerance–defense balance.