Project description:The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.
Project description:To show the similarity among MAIT-iPSCs, hiPSCs and hESCs and the gradual change of global gene expression of reMAIT cells along with differentiation, this experiment was designed. MAIT cells, MAIT-iPSCs, hiPSCs, hESCs, MAIT cells, and reMAIT cells at the several differerent stages of differentiation were collected. Then, they were applied in this experiment.
Project description:Natural killer (NK) cell function is regulated by a balance of activating and inhibitory signals, however the role of tumor necrosis factor (TNF) on NK cells remains poorly understood. The goal of this study was to use single-cell RNA sequencing to delineate the transcriptional changes induced in NK cells by TNF signalling through either TNFR1 or TNFR2. Our findings highlight the different regulatory pathways induced by each receptor which play dichotomous roles on the outcome of NK cell function and anti-bacterial immunity.
Project description:Natural killer (NK) cells have evolved to detect and kill aberrant cells with this activity being governed by the cytokine interleukin (IL)-15 and foreign and self-ligands. We have identified CIS (Cytokine-inducible SH2-containing protein; Cish gene) as the critical negative regulator of IL-15 signalling in NK cells. Cish was rapidly induced in response to IL-15 and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by superior proliferation, survival, IFN-γ production and cytotoxicity towards tumours. This was associated with enhanced JAK/STAT signalling in Cish-deleted NK cells. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish-/- mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. This study has uncovered a potent checkpoint in NK cell-mediated tumour immunity and holds promise for novel immunotherapies directed at blocking CIS function.
Project description:MAIT cells (MAITs) represent an abundant T lymphocyte subset with unique specificity for microbial metabolites presented by the MHC-1b molecule, MR1. MAIT conservation along evolution indicates important, non-redundant functions, but their low frequency in mice has hampered their detailed characterization. Here, we performed a transcriptomic analysis of murine MAITs in comparison with NKT subsets and with mainstream T cells in spleen and peripheral organs of B6-MAIT/CAST mice expressing a Rorc-GFP transgene. MAIT and NKT cells have been FACS-sorted after tetramer staining (MR1:5-OP-RU Tet+ for MAIT, CD1d:PBS57Tet+ for NKT), and 1/17 subsetting based on the expression of Rorc.
Project description:N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification on RNA. NK cells are the predominant innate lymphoid cells that mediate anti-viral and anti-tumor immunity. However, whether and how m6A modifications affect NK cell immunity remains unknown. Here, we discover that YTHDF2, a well-known m6A reader, is upregulated in NK cells upon activation by cytokines, tumors, and cytomegalovirus infection. Ythdf2 deficiency in NK cells impairs NK cell anti-tumor and anti-viral activity in vivo. YTHDF2 maintains NK cell homeostasis and terminal maturation, correlating with modulating NK cell trafficking and regulating Eomes, respectively. YTHDF2 promotes NK cell effector function and is required for IL-15-mediated NK cell survival and proliferation by forming a STAT5-YTHDF2 positive feedback loop. Transcriptome-wide screening identifies Tardbp to be involved in cell proliferation or survival as a YTHDF2-binding target in NK cells. Collectively, we elucidate the biological roles of m6A modifications in NK cells and highlight a new direction to harness NK cell anti-tumor immunity.
Project description:In mouse models, the bromodomain PHD finger transcription factor (BPTF) chromatin remodeling subunit in tumor cells suppresses natural killer (NK) cell antitumor activity. In vitro, BPTF suppresses NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating a conserved function.
