Dataset Information

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: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 (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-?, 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.

Project description:Introduction: The spleen plays an important role in regulating the immune response to infectious pathogens. T-cells dysfunction and exhaustion have been reported in patients with hepatitis B/C virus (HBV/HCV) infection, which contributes to persistent virus infection. The aims of this study were to investigate spleen-related evidence of immunosuppression and immune tolerance in HCV cirrhotic patients with portal hypertension (PH). Methods: The expression of programmed cell death 1 (PD-1), T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) and its ligand PD-L1/2, and Galectin-9 in the spleens and livers of HCV cirrhotic patients (n = 15) was analyzed using real-time PCR and immunohistochemistry. Flow cytometry was used to evaluate the expression of PD-1 and Tim-3 on splenic T-cells and the peripheral blood T-cells before and after splenectomy (n = 8). Results: Spleens from patients with PH showed significantly increased mRNA levels of PD-L2, Tim-3, Galectin-9, CD80, and CD86, and decreased levels of CD28 compared to control spleens (spleens removed due to traumatic injury) (all p < 0.05). Additionally, protein expression of inhibitory signaling molecules was significantly increased in both the spleens and livers of cirrhotic patients compared with controls (all p < 0.05). Peripheral blood and splenic CD4+ and CD8+ T-cells also expressed higher protein levels of PD-1, Tim-3, and CTLA-4 in cirrhotic patients as compared with healthy controls (all p < 0.05). The proportion of PD-1+CD4+T lymphocytes (26.2% ± 7.12% vs. 21.0% ± 9.14%, p = 0.0293) and Tim-3+CD8+ T lymphocytes (9.4% ± 3.04% vs. 6.0% ± 2.24%, p = 0.0175) in peripheral blood decreased followed splenectomy. Conclusion: The CD4+ and CD8+ T-cells in spleen and peripheral blood highly expressed PD-1 and Tim-3 in HCV-infected and cirrhotic patients with portal hypertension. Highly expressed PD-1 and Tim-3 in peripheral blood T-lymphocytes can be partly reversed following splenectomy.

Project description:Immune homeostasis depends upon effective clearance of pathogens while simultaneously preventing autoimmunity and immunopathology in the host. Restimulation-induced cell death (RICD) is one such mechanism where by activated T cells receive subsequent antigenic stimulation, reach a critical signal threshold through the T cell receptor (TCR), and commit to apoptosis. Many details of this process remain unclear, including the role of co-stimulatory and co-inhibitory proteins that influence the TCR signaling cascade. Here we characterize the role of T cell immunoglobulin and mucin domain containing 3 (TIM-3) in RICD regulation. TIM-3 protected newly activated CD8+ effector T cells from premature RICD during clonal expansion. Surprisingly, however, we found that TIM-3 potentiated RICD in late-stage effector T cells. The presence of TIM-3 increased proximal TCR signaling and proapoptotic protein expression in late-stage effector T cells, with no consistent signaling effects noted in newly activated cells with or without TIM-3. To better explain these differences in TIM-3 function as T cells aged, we characterized the temporal pattern of TIM-3 expression in effector T cells. We found that TIM-3 was expressed on the surface of newly activated effector T cells, but remained largely intracellular in late-stage effector cells. Consistent with this, TIM-3 required a ligand to prevent early RICD, whereas ligand manipulation had no effects at later stages. Of the known TIM-3 ligands, carcinoembryonic antigen-related cell adhesion molecule (CEACAM1) showed the greatest difference in surface expression over time and also protected newly activated cells from premature RICD, with no measurable effects in late-stage effectors. Indeed, CEACAM1 enabled TIM-3 surface expression on T cells, implying a co-dependency for these proteins in protecting expanding T cells from premature RICD. Our findings suggest that co-signaling proteins like TIM-3 and CEACAM1 can alter RICD sensitivity at different stages of the effector T cell response, with important implications for checkpoint blockade therapy.

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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