Tissue‐resident CD8⁺T memory cells with unique properties are present in human decidua during early pregnancy

Abstract

Problem Resident memory T (TRM) cells reside in the uterus during pregnancy may play an important role in balancing maternal‐fetal tolerance with anti‐infectious immunity. Although CD8+TRM and decidual CD8+T cells have been extensively characterized, the properties of decidual CD8+TRM (dTRM) cells remain poorly defined. Method of study We investigated the heterogeneity, phenotypes, and functions of dTRM cells, and compared the proportion of dTRM cells between normal pregnancy and recurrent spontaneous abortion (RSA) using flow cytometry. Moreover, we cocultured peripheral CD8+T (CD8+pT) cells with trophoblast, or decidual stomal cells (DSCs) in the presence or absence of anti‐TGF‐β antibody or TGF‐β type I receptor inhibitor to explore the effects of maternal‐fetal environment on decidual CD8+TRM cell formation. Results We found that CD69+CD103+TRM cells were abundant in CD8+dT cells but not in CD4+dT cells with effector‐memory (EM, CD45RA−CCR7−) phenotypes. The percentage of dTRM cells from RSA patients was significantly higher than that from normal pregnancy. Furthermore, dTRM cells showed increased expressions of chemokine receptors, T‐cell exhaustion‐related molecules, and produced more anti‐inflammatory cytokines and effector cytokines upon stimulation. Moreover, DSCs produced a considerable level of TGF‐β and upregulated CD103 expression on CD69+CD8+pT cells, which can be significantly reversed by blocking TGF‐β receptor. Conclusion Our findings demonstrate that TRM cells with unique properties are present in the decidua during human early pregnancy. They possess an enhanced capacity to produce effector cytokines and regulatory molecules, which might be important in the balance between maternal‐fetal immune tolerance and the capacity to aggressively respond to infections.

Human Tissue-Resident Memory T Cells in the Maternal–Fetal Interface. Lost Soldiers or Special Forces?

“…While CD103 coexpression in CD69 + CD8 T cells in the first-trimester decidua is markedly less than what is observed in other mucosal tissues [45,57,58], it suggests that some degree of TGF-β signaling [67] may occur at the maternal-fetal interface [68]. Although these studies detected a large fraction of CD69-expressing T cells (approximately 75% of CD8s and 50% of CD4s) within the decidua, sizable populations of Tcm and naïve T cells were also detected, indicating the presence of (contaminating) blood ( Figure 1C) and possibly even underestimated frequencies of Trm cells [66]. Transcriptomic studies of tissues from 6-14 weeks gestation echoed Trm findings, as SELL (encodes CD62L) transcripts were lower and CD69, PDCD1 (encodes PD-1), ITGA1 (encodes CD49a), and ITGAE (encodes CD103) were enriched in decidual T cells [11].…”

“…Following the extensive tissue remodeling to the endometrium postimplantation, the resulting decidua also harbors Trm cells. In the early stages of pregnancy, in which trophoblast invasion is shallow, a major subset of Tem cells express CD69 (with a lesser fraction of coexpressing CD103 within CD8 T cells) [66]. While CD103 coexpression in CD69 + CD8 T cells in the first-trimester decidua is markedly less than what is observed in other mucosal tissues [45,57,58], it suggests that some degree of TGF-β signaling [67] may occur at the maternal-fetal interface [68].…”

Regulation of the innate immune cells during pregnancy: An immune checkpoint perspective

“…Furthermore, these cells showed high expression of the chemokine receptors, T‐cell exhaustion‐related molecules, and co‐inhibitory molecules PD‐1, CTLA‐4 and LAG3 86,87,89,111 . Moreover, they produced more anti‐inflammatory cytokines and effector cytokines after stimulation 111 . The tissue‐resident molecules CD103 and CXCR3 were increased significantly with almost no perforin secretion in the CD8 + dT cells compared to the CD8 + pT cells.…”

“…Compared to the peripheral blood, the tissue‐resident molecules CD103 and CXCR3 are increased significantly with almost no perforin secretion in the CD8 + dT cells, indicating that the decidual microenvironment is essential for the residency of the CD8 + T cells 86 . Furthermore, these cells showed high expression of the chemokine receptors, T‐cell exhaustion‐related molecules, and co‐inhibitory molecules PD‐1, CTLA‐4 and LAG3 86,87,89,111 . Moreover, they produced more anti‐inflammatory cytokines and effector cytokines after stimulation 111 .…”

The Role of Immune Cells in Recurrent Spontaneous Abortion

“…In the decidua, CD8 + T cells can also produce effector cytokines and regulatory molecules. A significant elevation in the proportion of decidual CD8 + cells was observed in RSA patients, which may also be related to the poor balance between maternal-fetal immune tolerance [ 103 ]. Human CD4 + T helper cells assist in regulating the immune response, particularly in pregnancy and delivery [ 104 ], by releasing a large amount of cytokines.…”