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The appropriate frequency and function of decidual Tim-3⁺CTLA-4⁺CD8⁺ T cells are important in maintaining normal pregnancy.

ABSTRACT: Maternal decidual CD8⁺ T (dCD8⁺ T) cells must integrate the antithetical demands of maternal-fetal tolerance and anti-viral immunity to establish a successful pregnancy. T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two important co-inhibitory molecules that regulating CD8⁺ T cells responses during infection and tumor. In the present study, we examined the co-expression of Tim-3 and CTLA-4 on CD8⁺ T cells during pregnancy and found the higher frequency of Tim-3⁺CTLA-4⁺dCD8⁺ T cells in response to trophoblasts. This Tim-3⁺CTLA-4⁺dCD8⁺ T cells subset showed an active status and produced more anti-inflammatory cytokines. Furthermore, the decreased number and altered function of Tim-3⁺CTLA-4⁺dCD8⁺ T cells correlated to miscarriage. Combined blocking Tim-3 and CTLA-4 pathways were highly effective in inhibiting the production of anti-inflammatory cytokines and were detrimental to the maintenance of pregnancy. Together, these findings supported that Tim-3 and CTLA-4 pathways might play positive roles in the establishment and/or maintenance of maternal-fetal tolerance so to promote the maintenance of normal pregnancy. So the reproductive safety must be considered, especially when anti-Tim-3/CTLA-4 antibody (and other immune checkpoint inhibitors) are used in pregnancy.

SUBMITTER: Wang S

PROVIDER: S-EPMC6538701 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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The appropriate frequency and function of decidual Tim-3+CTLA-4+CD8+ T cells are important in maintaining normal pregnancy.

Wang Songcun S Sun Fengrun F Li Mengdie M Qian Jinfeng J Chen Chunqin C Wang Mingyan M Zang Xingxing X Li Dajin D Yu Min M Du Meirong M

Cell death & disease 20190528 6

Maternal decidual CD8+ T (dCD8+ T) cells must integrate the antithetical demands of maternal-fetal tolerance and anti-viral immunity to establish a successful pregnancy. T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two important co-inhibitory molecules that regulating CD8+ T cells responses during infection and tumor. In the present study, we examined the co-expression of Tim-3 and CTLA-4 on CD8+ T ...[more]

PMID: 31138782

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Project description:BackgroundDuring 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.MethodsWe 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.ResultsWe found that, compared with CD8+pT cells, CD8+dT cells consisted mainly of effector memory cells (TEM) and terminally differentiated effector memory cells (TEMRA). Both TEM and TEMRA 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.ConclusionsOur 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.

Project description:BackgroundWomen in early pregnancy infected by Toxoplasma gondii may have severe adverse pregnancy outcomes, such as spontaneous abortion and fetal malformation. The inhibitory molecule T cell immunoglobulin and mucin domain 3 (Tim-3) is highly expressed on decidual dendritic cells (dDCs) and plays an important role in maintaining immune tolerance. However, whether T. gondii infection can cause dDC dysfunction by influencing the expression of Tim-3 and further participate in adverse pregnancy outcomes is still unclear.MethodsAn abnormal pregnancy model in Tim-3-deficient mice and primary human dDCs treated with Tim-3 neutralizing antibodies were used to examine the effect of Tim-3 expression on dDC dysfunction after T. gondii infection.ResultsFollowing T. gondii infection, the expression of Tim-3 on dDCs was downregulated, those of the pro-inflammatory functional molecules CD80, CD86, MHC-II, tumor necrosis factor-α (TNF-α), and interleukin-12 (IL-12) were increased, while those of the tolerant molecules indoleamine 2,3-dioxygenase (IDO) and interleukin-10 (IL-10) were significantly reduced. Tim-3 downregulation by T. gondii infection was closely associated with an increase in proinflammatory molecules and a decrease in tolerant molecules, which further resulted in dDC dysfunction. Moreover, the changes in Tim-3 induced by T. gondii infection further reduced the secretion of the cytokine IL-10 via the SRC-signal transducer and activator of transcription 3 (STAT3) pathway, which ultimately contributed to abnormal pregnancy outcomes.ConclusionsToxoplasma gondii infection can significantly downregulate the expression of Tim-3 and cause the aberrant expression of functional molecules in dDCs. This leads to dDC dysfunction, which can ultimately contribute to abnormal pregnancy outcomes. Further, the expression of the anti-inflammatory molecule IL-10 was significantly decreased by Tim-3 downregulation, which was mediated by the SRC-STAT3 signaling pathway in dDCs after T. gondii infection.

Dataset Information

The appropriate frequency and function of decidual Tim-3⁺CTLA-4⁺CD8⁺ T cells are important in maintaining normal pregnancy.

Publications

The appropriate frequency and function of decidual Tim-3<sup>+</sup>CTLA-4<sup>+</sup>CD8<sup>+</sup> T cells are important in maintaining normal pregnancy.

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