Foxp3 + regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and ''toxic'' gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6-and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.
Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm resulting from the malignant transformation of myeloid progenitors. Despite intensive chemotherapy leading to initial treatment responses, relapse caused by intrinsic or acquired drug resistance represents a major challenge. Here, we report that histone 3 lysine 27 demethylase KDM6A (UTX) is targeted by inactivating mutations and mutation-independent regulation in relapsed AML. Analyses of matched diagnosis and relapse specimens from individuals with KDM6A mutations showed an outgrowth of the KDM6A mutated tumor population at relapse. KDM6A expression is heterogeneously regulated and relapse-specific loss of KDM6A was observed in 45.7% of CN-AML patients. KDM6A-null myeloid leukemia cells were more resistant to treatment with the chemotherapeutic agents cytarabine (AraC) and daunorubicin. Inducible re-expression of KDM6A in KDM6A-null cell lines suppressed proliferation and sensitized cells again to AraC treatment. RNA expression analysis and functional studies revealed that resistance to AraC was conferred by downregulation of the nucleoside membrane transporter ENT1 (SLC29A1) by reduced H3K27 acetylation at the ENT1 locus. Our results show that loss of KDM6A provides cells with a selective advantage during chemotherapy, which ultimately leads to the observed outgrowth of clones with KDM6A mutations or reduced KDM6A expression at relapse.
Multidimensional single cell-analyses of T cells have fueled the debate about either extensive plasticity or “mixed” priming of T helper cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of T helper cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system in a model of multiple sclerosis are distinct. i-T cells were Cxcr6 + and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter while i-T cells were also recruited to grey matter. Therefore, we propose that the definition of T helper cell subsets by their site of priming might guide an advanced understanding of T helper cell biology in health and disease.
scheel@helmholtz-muenchen.de and 39 Martin R. Sprick, m.sprick@Dkfz-Heidelberg.de and 40 Andreas Trumpp, a.trumpp@Dkfz-Heidelberg.de 41 42 Running title: 43 Epithelial gene expression in EMT is required for breast cancer metastasis. 44 45 Abstract 48Despite important advances in the treatment of breast cancer, the 5-year survival rate 49 for patients with distant metastasis remains less than 30%. Metastasis is a complex, 50 multi-step process beginning with local invasion and ending with the outgrowth of 51 systemically disseminated cells into actively proliferating metastases that ultimately 52 cause the destruction of vital organs. It is this last step that limits patient survival and, 53 at the same time, remains the least understood mechanistically. Here, we focus on 54 understanding determinants of metastatic outgrowth using metastatic effusion biopsies 55 from stage IV breast cancer patients. By modelling metastatic outgrowth through 56 xenograft transplantation, we show that tumour initiation potential of patient-derived 57 metastatic breast cancer cells across breast cancer subtypes is strongly linked to high 58 levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly 59 plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt 60 mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels 61 are caused by the irreversible reprogramming to a mesenchymal state with 62 concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to 63 retain epithelial traits is tied to a global epigenetic program that limits the actions of 64 EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide 65 direct evidence that maintenance of epithelial identity is required for metastatic 66 outgrowth while concomitant expression of mesenchymal markers enables plasticity. 67In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal 68 reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our 69 data provide a framework for the intricate intercalation of mesenchymal and epithelial 70 traits in metastatic growth. 71Other studies emphasize that a transient, rather than permanent expression of EMT-87 transcription factors is crucial for the outgrowth of metastases 4,6,7 . This is supported by 88 the finding that most macroscopic metastases generated by carcinomas display an 89 epithelial morphology 8 . However, a strict requirement for EMT at any time during the 90 metastatic process is called into question by the finding that overexpression of micro 91RNAs that inhibit EMT does not affect metastasis 9 and loss of Twist1 and Snai1 92 expression in a pancreatic cancer mouse model does not change invasion and disease 93 progression 10 . 94More complication has recently arisen from the observation that tumour cells with an 95 intermediate, often termed hybrid epithelial-mesenchymal phenotype, are the most 96 competent in colonization and metastasis fo...
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