Despite multiple associations between the microbiota and immune diseases, their role in autoimmunity is poorly understood. We found that translocation of a gut pathobiont, Enterococcus gallinarum, to the liver and other systemic tissues triggers autoimmune responses in a genetic background predisposing to autoimmunity. Antibiotic treatment prevented mortality in this model, suppressed growth of E. gallinarum in tissues, and eliminated pathogenic autoantibodies and Tcells. Hepatocyte–E. gallinarum cocultures induced autoimmune-promoting factors. Pathobiont translocation in monocolonized and autoimmune-prone mice induced autoantibodies and caused mortality, which could be prevented by an intramuscular vaccine targeting the pathobiont. E. gallinarum–specific DNA was recovered from liver biopsies of autoimmune patients, and cocultures with human hepatocytes replicated the murine findings; hence, similar processes apparently occur in susceptible humans. These discoveries show that a gut pathobiont can translocate and promote autoimmunity in genetically predisposed hosts.
Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancer tissue and block immune cell effector functions. Lack of mechanistic insight 54 into MDSC suppressive activity and a marker for their identification hampered attempts to 55 overcome T cell-inhibition and unleash anti-cancer immunity. Here we report that human MDSCs 56 were characterized by strongly reduced metabolism and conferred this compromised metabolic 57 state to CD8 + T cells thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl-radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase (SSAO), to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8 + T cells. In a murine cancer model, neutralization of dicarbonyl-activity overcame MDSC-mediated T cell-suppression and together with checkpoint inhibition improved efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as marker metabolite for MDSCs that mediates T cell paralysis and can serve as target to improve cancer immune therapy. Results 92 Dormant metabolic phenotype in MDSCs 93Suppressive myeloid cells arise during chronic inflammation in tissues 17 , and tissue stromal cells 94 induce transition of monocytes into monocytic MDSCs 16 . We exploited this capacity of stromal cells to convert human peripheral blood monocytes into MDSCs, which are phenotypically similar 96 to CD14 + HLA-DR -/low suppressive myeloid cells directly isolated from cancer patients 16 , to characterize the mechanism of MDSC-mediated T cell suppression. Transcriptome analysis showed less than 200 differentially expressed genes between MDSCs and monocytes, which did not include surface molecules suitable for phenotypic discrimination or known immune suppressive mediators to explain their suppressive activity (supplementary table I-IV, Extended Data Fig. 1). Consistently, blockade of known immune suppressive mediators did not prevent MDSC-mediated T cell suppression (Extended Data Fig. 2). Surprisingly, we found downregulation of genes encoding glycolysis-related enzymes in MDSCs (Fig. 1a, and Extended Data Table V).Indeed, MDSCs showed reduced glucose uptake and Glut1 surface expression (Fig. 1b), the main transporter mediating glucose uptake in immune cells. As predicted from gene expression analysis, hexokinase activity was lower in MDSCs (Fig. 1c). To validate these results, we isolated CD14 + HLA-DR -/lo cells from tumor tissue of patients with hepatocellular carcinoma by enzymatic digestion followed by density centrifugation and flow cytometric cell sorting. We confirmed reduced glucose uptake and hexokinase activity in CD14 + HLA-DR -/low cells isolated from tumor tissue of cancer patients (Fig. 1d,e, and Extended Data Table VI), which are considered to represent MDSCs. Strikingly, MDSCs failed to utilize glucose for glycolysis and also showed reduced cellular bioenergetics, i.e. lower mitochondrial membrane potential quantified by the potentiometric mitochondrial ...
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.
PMN-MDSCs (polymorphonuclear myeloid-derived suppressor cells) have been characterized in the context of malignancies. Here we found that PMN-MDSCs had the unique ability to restrain B cell accumulation during central nervous system (CNS) autoimmunity. Ly6G + cells were recruited to the CNS during experimental autoimmune encephalomyelitis (EAE), interacted with B cells that produced the cytokines GM-CSF and IL-6, and acquired properties of PMN-MDSCs in the CNS in a manner dependent on the signal transducer STAT3. Depletion of Ly6G + cells or dysfunction of Ly6G + cells through conditional ablation of STAT3 resulted in the selective accumulation of GM-CSF-producing B cells in the CNS compartment, which in turn promoted an activated microglial phenotype and failure to recover from EAE. The frequency of CD138 + B cells in the cerebrospinal fluid (CSF) of human patients with multiple sclerosis negatively correlated with the frequency of PMN-MDSCs in the CSF. Thus, PMN-MDSCs might selectively control the accumulation and cytokine secretion of B cells within the inflamed CNS.
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