Decidual natural killer (dNK) cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) are expressed on over 60% of dNK cells. Tim-3 1 dNK cells display higher interleukin (IL)-4 and lower tumor necrosis factor (TNF)-a and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 (Gal-9) and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper (Th)2-type cytokines were decreased and Th1-type cytokines were increased in Tim-3 1 but not Tim-3 2 dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.

Pregnancy loss occurs in about 15% of clinically recognized pregnancies, and defective maternal-fetal immune tolerance contributes to more than 50% of these events. We found that signaling by the type I membrane protein T cell immunoglobulin and mucin-containing protein 3 (Tim-3) in natural killer (NK) cells had an essential protective role during early pregnancy. Tim-3 on peripheral NK (pNK) cells was transiently increased in abundance during the first trimester of pregnancy, which depended on interleukin-4 (IL-4)-signal transducer and activator of transcription 6 (STAT6) and progesterone signaling. Tim-3 pNK cells displayed immunosuppressive activities, including the production of anti-inflammatory cytokines and the induction of regulatory T cells (T) in a transforming growth factor-β1 (TGF-β1)-dependent manner. Tim-3 on pNK cells was stimulated by its ligand galectin-9 (Gal-9), leading to signaling by the kinases c-Jun N-terminal kinase (JNK) and AKT. In recurrent miscarriage (RM) patients, Tim-3 abundance on pNK cells was reduced and the immunosuppressive activity of Tim-3 pNK cells was impaired. Compared to Tim-3 pNK cells from donors with normal pregnancies, RM patient Tim-3 pNK cells exhibited changes in DNA accessibility in certain genetic loci, which were reversed by inhibiting accessible chromatin reader proteins. Furthermore, Tim-3 pNK cells, but not Tim-3 pNK cells, reduced fetal loss in abortion-prone and NK cell-deficient mice. Together, our findings reveal a critical role for Tim-3-Gal-9 signaling-mediated immunoregulation by pNK cells in maternal-fetal immune tolerance and suggest that Tim-3 abundance on pNK cells is a potential biomarker for RM diagnosis.

Background: Anti-SARS-CoV-2 virus antibody levels in convalescent plasma (CP), which may be useful in severe Anti-SARS-CoV-2 virus infections, have been rarely reported. Results: A total of eight donors were considered for enrollment; two of them were excluded because of ineligible routine check. Of the six remaining participants, five samples were tested weakly positive by the IgM ELISA. Meanwhile, high titers of IgG were observed in five samples. The patient treated with CP did not require mechanical ventilation 11 days after plasma transfusion, and was then transferred to a general ward. Conclusions: Our serological findings in convalescent plasma from recovered patients may help facilitate understanding of the SARS-CoV-2 infection and establish CP donor screening protocol in COVID-19 outbreak. Methods: Anti-SARS-CoV-2 antibodies including IgM and IgG were measured by two enzyme-linked immunosorbent assays (ELISA) in convalescent plasma from six donors who have recovered from coronavirus disease 2019 (COVID-19) in Nanjing, China. CP was also utilized for the treatment of one severe COVID-19 patient.

Although one of the first comprehensive examinations of long non-coding RNA (lncRNA) expression was performed in human CD8 T lymphocytes, little is known about their roles in CD8 T cells functions during the progression of hepatocellular carcinoma (HCC). Here, we show that Lnc-Tim3 is upregulated and negatively correlates with IFN-γ and IL-2 production in tumor-infiltrating CD8 T cells of HCC patients. Lnc-Tim3 plays a pivotal role in stimulating CD8 T exhaustion and the survival of the exhausted CD8 T cells. Mechanistically, Lnc-Tim3 specifically binds to Tim-3 and blocks its interaction with Bat3, thus suppressing downstream Lck/ NFAT1/AP-1 signaling, leading to nuclear localization of Bat3, and enhancing p300-dependent p53 and RelA transcriptional activation of anti-apoptosis genes including MDM2 and Bcl-2. In summary, Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity, suggesting that Lnc-Tim3 and its associated signaling pathways may influence the outcome of cancer therapies aimed at modulating the acquired immune system.

Physiological pregnancy requires the maternal immune system to recognize and tolerate embryonic Ags. Although multiple mechanisms have been proposed, it is not yet clear how the fetus evades the maternal immune system. In this article, we demonstrate that trophoblast-derived thymic stromal lymphopoietin (TSLP) instructs decidual CD11c+ dendritic cells (dDCs)with increased costimulatory molecules; MHC class II; and Th2/3-type, but not Th1-type, cytokines. TSLP-activated dDCs induce proliferation and differentiation of decidual CD4+CD25− T cells into CD4+CD25+FOXP3+ regulatory T cells (Tregs) through TGF-β1. TSLP-activated dDC–induced Tregs display immunosuppressive features and express Th2-type cytokines. In addition, decidual CD4+CD25+FOXP3+ Tregs promote invasiveness and HLA-G expression of trophoblasts, resulting in preferential production of Th2 cytokines and reduced cytotoxicity in decidual CD56brightCD16− NK cells. Of interest, decreased TSLP expression and reduced numbers of Tregs were observed at the maternal–fetal interface during miscarriage. Our study identifies a novel feedback loop between embryo-derived trophoblasts and maternal decidual leukocytes, which induces a tolerogenic immune response to ensure a successful pregnancy.