Modulation of central tolerance through RANKL alters thymic output and enhances anti-tumor immunity.
Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well understood. Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared with females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity.
Summary Epigenetic changes, including histone methylation, control T cell differentiation and memory formation, though the enzymes that mediate these processes are not clear. We show that UTX, a histone H3 lysine 27 (H3K27) demethylase, supports T follicular helper (Tfh) cell responses that are essential for B cell antibody generation and the resolution of chronic viral infections. Mice with a T cell-specific UTX deletion had fewer Tfh cells, reduced germinal center responses, lacked virus-specific IgG, and were unable to resolve chronic lymphocytic choriomeningitis virus infections. UTX-deficient T cells showed decreased expression of interleukin-6 receptor-α and other Tfh cell-related genes that were associated with increased H3K27 methylation. Additionally, Turner Syndrome subjects, who are predisposed to chronic ear infections, had reduced UTX expression in immune cells and decreased circulating CD4+ CXCR5+ T cell frequency. Thus, we identify a critical link between UTX in T cells and immunity to infection.
Extracellular electron transfer (EET) is a strategy for respiration in which electrons generated from metabolism are moved outside the cell to a terminal electron acceptor, such as iron or manganese oxide. EET has primarily been studied in two model systems, Shewanella oneidensis and Geobacter sulfurreducens. Metal reduction has also been reported in numerous microorganisms, including Aeromonas spp., which are ubiquitous Gammaproteobacteria found in aquatic ecosystems, with some species capable of pathogenesis in humans and fish. Genomic comparisons of Aeromonas spp. revealed a potential outer membrane conduit homologous to S. oneidensis MtrCAB. While the ability to respire metals and mineral oxides is not widespread in the genus Aeromonas, 90% of the sequenced Aeromonas hydrophila isolates contain MtrCAB homologs. A. hydrophila ATCC 7966 mutants lacking mtrA are unable to reduce metals. Expression of A. hydrophila mtrCAB in an S. oneidensis mutant lacking homologous components restored metal reduction. Although the outer membrane conduits for metal reduction were similar, homologs of the S. oneidensis inner membrane and periplasmic EET components CymA, FccA, and CctA were not found in A. hydrophila. We characterized a cluster of genes predicted to encode components related to a formate-dependent nitrite reductase (NrfBCD), here named NetBCD (for Nrf-like electron transfer), and a predicted diheme periplasmic cytochrome, PdsA (periplasmic diheme shuttle). We present genetic evidence that proteins encoded by this cluster facilitate electron transfer from the cytoplasmic membrane across the periplasm to the MtrCAB conduit and function independently from an authentic NrfABCD system. A. hydrophila mutants lacking pdsA and netBCD were unable to reduce metals, while heterologous expression of these genes could restore metal reduction in an S. oneidensis mutant background. EET may therefore allow A. hydrophila and other species of Aeromonas to persist and thrive in iron-or manganese-rich oxygenlimited environments. IMPORTANCE Metal-reducing microorganisms are used for electricity production, bioremediation of toxic compounds, wastewater treatment, and production of valuable compounds. Despite numerous microorganisms being reported to reduce metals, the molecular mechanism has primarily been studied in two model systems, Shewanella oneidensis and Geobacter sulfurreducens. We have characterized the mechanism of extracellular electron transfer in Aeromonas hydrophila, which uses the well-studied Shewanella system, MtrCAB, to move electrons across the outer membrane; however, most Aeromonas spp. appear to use a novel mechanism to transfer electrons from the inner membrane through the periplasm and to the outer membrane. The conserved use of MtrCAB in Shewanella spp. and Aeromonas spp. for metal reduction and conserved genomic architecture of metal reduction genes in Aeromonas spp. may serve as genomic markers for identifying metal-reducing microorganisms from genomic or transcriptomic sequencing. Understanding the variety of
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.