ABSTRACT
Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T 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 helper T 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 (CNS) in a model of multiple sclerosis (MS) 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 gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.
Subject(s)
Autoimmunity , Brain/immunology , Cell Lineage , Encephalomyelitis, Autoimmune, Experimental/immunology , Intestines/immunology , Skin/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adoptive Transfer , Animals , Autoimmunity/drug effects , Brain/drug effects , Brain/metabolism , Calcium Signaling , Cerebrospinal Fluid/immunology , Cerebrospinal Fluid/metabolism , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Fingolimod Hydrochloride/pharmacology , Gene Expression Profiling , Genes, T-Cell Receptor , HEK293 Cells , Humans , Immunosuppressive Agents/pharmacology , Intestines/drug effects , Intravital Microscopy , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Fluorescence , Multiple Sclerosis, Relapsing-Remitting/genetics , Multiple Sclerosis, Relapsing-Remitting/immunology , Multiple Sclerosis, Relapsing-Remitting/metabolism , Phenotype , Prospective Studies , RNA-Seq , Receptors, CXCR6/genetics , Receptors, CXCR6/metabolism , Receptors, Purinergic P2X7/genetics , Receptors, Purinergic P2X7/metabolism , Single-Cell Analysis , Skin/drug effects , Skin/metabolism , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Helper-Inducer/transplantation , TranscriptomeABSTRACT
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.