Decidual CD8+T cells exhibit both residency and tolerance signatures modulated by decidual stromal cells
Lu Liu, Xixi Huang, Chun‐Fang Xu, Chunqin Chen, Weijie Zhao, Da‐Jin Li, Liping Li, Li Wang, Meirong Du
Abstract
Abstract Background 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. Methods 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. Results 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. Conclusions 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.