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Animal cytokinesis ends with the formation of a thin intercellular membrane bridge that connects the two newly formed sibling cells, which is ultimately resolved by abscission. Whilemitosis is completed within 15 min, the intercellular bridge can persist for hours, maintaining a physical connection between sibling cells and allowing exchange of cytosolic components. Although cell–cell communication is fundamental for development, the role of intercellular bridges during embryogenesis has not been fully elucidated. In this work, we characterized the spatiotemporal characteristics of the intercellular bridge during early zebrafish development. We found that abscission is delayed during the rapid division cycles that occur in the early embryo, giving rise to the formation of interconnected cell clusters. Abscission was accelerated when the embryo entered the midblastula transition (MBT) phase. Components of the ESCRT machinery, which drives abscission, were enriched at intercellular bridges post-MBT and, interfering with ESCRT function, extended abscission beyond MBT. Hallmark features of MBT, including transcription onset and cell shape modulations, were more similar in interconnected sibling cells compared to other neighboring cells. Collectively, our findings suggest that delayed abscission in the early embryo allows clusters of cells to coordinate their behavior during embryonic development.

In the version of this article initially published, three authors (Hui-Fern Kuoy, Adam P. Uldrich and Dale. I. Godfrey) and their affiliations, acknowledgments and contributions were not included. The correct information is as follows:

[gamma][delta] T cells are situated at barrier sites and guard the body from infection and damage. However, little is known about their roles outside of host defense in nonbarrier tissues. Here, we characterize a highly enriched tissue-resident population of [gamma][delta] T cells in adipose tissue that regulate age-dependent regulatory T cell (T.sub.reg) expansion and control core body temperature in response to environmental fluctuations. Mechanistically, innate PLZF.sup.+ [gamma][delta] T cells produced tumor necrosis factor and interleukin (IL) 17 A and determined PDGFR[alpha].sup.+ and Pdpn.sup.+ stromal-cell production of IL-33 in adipose tissue. Mice lacking [gamma][delta] T cells or IL-17A exhibited decreases in both ST2.sup.+ T.sub.reg cells and IL-33 abundance in visceral adipose tissue. Remarkably, these mice also lacked the ability to regulate core body temperature at thermoneutrality and after cold challenge. Together, these findings uncover important physiological roles for resident [gamma][delta] T cells in adipose tissue immune homeostasis and body-temperature control.

Regulatory T cells (Tregs), characterized by FOXP3 expression, are essential for maintaining immune homeostasis by controlling inflammation. However, in autoimmune diseases such as rheumatoid arthritis (RA), impaired Treg function contributes to immune dysregulation and disease pathology. While most studies of human Tregs have focused on blood, here we analyzed Tregs in synovial tissues from RA patients using single cell RNA sequencing (scRNAseq). We identified two predominant Treg states, CD25 CXCR6 Tregs with strong suppressive function, and CD25 AREG Tregs, a dysfunctional state exclusively enriched in synovial tissues but not in blood. Computational and in vitro analyses revealed that cortisol induced AREG expression, suppressed glycolysis, and impaired the suppressive function of CD25 AREG Tregs. In turn, AREG promoted an IL-33 inflammatory phenotype in synovial fibroblasts. Importantly, we found that TNFR2 engagement can prevent or reverse this dysfunctional Treg state. In contrast to CD25 AREG Tregs, CD25 CXCR6 Tregs were highly suppressive, showed coordinated abundance with macrophages in synovial tissue, and functionally interacted with membrane-bound TNFα expressed by macrophages, which promoted their functional suppressive state. These two Treg subsets were similarly found in the synovial tissue in Juvenile Idiopathic Arthritis (JIA), another inflammatory arthritic disorder, indicating conserved mechanisms across arthritic diseases. Together, our findings define distinct pathways driving divergent functional and dysfunctional Treg states in inflamed tissues and point to interventions that may prevent or reverse the development of the dysfunctional state.

In the version of this article initially published, three authors (Hui-Fern Kuoy, Adam P. Uldrich and Dale. I. Godfrey) and their affiliations, acknowledgments and contributions were not included. The correct information is as follows: Ayano C. Kohlgruber 1,2 , Shani T. Gal-Oz 3 , Nelson M. LaMarche 1,2 , Moto Shimazaki 1 , Danielle Duquette 4 , Hui-Fern Koay 5,6 , Hung N. Nguyen 1 , Amir I. Mina 4 , Tyler Paras 1 , Ali Tavakkoli 7 , Ulrich von Andrian 2,8 , Adam P. Uldrich 5,6 , Dale I. Godfrey 5,6 , Alexander S. Banks 4 , Tal Shay 3 , Michael B. Brenner 1,10 * and Lydia Lynch 1,4,9,10 * 1 Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA, USA. 2 Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. 3 Department of Life Sciences, Ben-Gurion University of the Negev, Beersheba, Israel. 4 Division of Endocrinology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA. 5 Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia. 6 ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Australia. 7 Department of General and Gastrointestinal Surgery, Brigham and Women’s Hospital, Boston, MA, USA. 8 Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA. 9 School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. 10 These authors jointly supervised this work: Michael B. Brenner, Lydia Lynch. *e-mail: mbrenner@research.bwh.harvard.edu; llynch@bwh.harvard.edu Acknowledgements We thank A.T. Chicoine, flow cytometry core manager at the Human Immunology Center at BWH, for flow cytometry sorting. We thank D. Sant’Angelo (Rutgers Cancer Institute) for providing Zbtb16 –/– mice and R. O’Brien (National Jewish Health) for providing Vg4/6 –/– mice. Supported by NIH grant R01 AI11304603 (to M.B.B.), ERC Starting Grant 679173 (to L.L.), the National Health and Medical Research Council of Australia (1013667), an Australian Research Council Future Fellowship (FT140100278 for A.P.U.) and a National Health and Medical Research Council of Australia Senior Principal Research Fellowship (1117766 for D.I.G.). Author contributions A.C.K., L.L., and M.B.B. conceived and designed the experiments, and wrote the manuscript. A.C.K., N.M.L., L.L., H.N.N., M.S., T.P., and D.D. performed the experiments. S.T.G.-O. and T.S. performed the RNA-seq analysis. A.S.B. and A.I.M. provided advice and performed the CLAMS experiments. A.T. provided human bariatric patient samples. Parabiosis experiments were performed in the laboratory of U.v.A. H.-F.K., A.P.U. and D.I.G provided critical insight into the TCR chain usage of PLZF + γδ T cells. M.B.B., N.M.L., and L.L. critically reviewed the manuscript. The errors have been corrected in the HTML and PDF version of the article. Correction to: Nature Immunology doi:10.1038/s41590-018-0094-2 (2018), published online 18 April 2018.

γδ T cells are situated at barrier sites and guard the body from infection and damage. However, little is known about their roles outside of host defense in nonbarrier tissues. Here, we characterize a highly enriched tissue-resident population of γδ T cells in adipose tissue that regulate age-dependent regulatory T cell (T reg ) expansion and control core body temperature in response to environmental fluctuations. Mechanistically, innate PLZF + γδ T cells produced tumor necrosis factor and interleukin (IL) 17 A and determined PDGFRα + and Pdpn + stromal-cell production of IL-33 in adipose tissue. Mice lacking γδ T cells or IL-17A exhibited decreases in both ST2 + T reg cells and IL-33 abundance in visceral adipose tissue. Remarkably, these mice also lacked the ability to regulate core body temperature at thermoneutrality and after cold challenge. Together, these findings uncover important physiological roles for resident γδ T cells in adipose tissue immune homeostasis and body-temperature control. Lynch, Brenner and colleagues find that tissue-resident γδ T cells reside in adipose tissues in both mice and humans. These cells play essential roles in regulating thermogenesis and supporting age-dependent increases in adipose-tissue regulatory T cell populations.

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states can drive fibrosis, inflammation, and tissue destruction. In the joint synovium, fibroblasts provide homeostatic maintenance and lubrication. Little is known about what regulates the homeostatic functions of fibroblasts in healthy conditions. We performed RNA sequencing of healthy human synovial tissue and identified a fibroblast gene expression program characterized by enhanced fatty acid metabolism and lipid transport. We found that fat-conditioned media reproduces key aspects of the lipid-related gene signature in cultured fibroblasts. Fractionation and mass spectrometry identified cortisol in driving the healthy fibroblast phenotype, confirmed using glucocorticoid receptor gene ( ) deleted cells. Depletion of synovial adipocytes in mice resulted in loss of the healthy fibroblast phenotype and revealed adipocytes as a major contributor to active cortisol generation via β expression. Cortisol signaling in fibroblasts mitigated matrix remodeling induced by TNFα- and TGFβ, while stimulation with these cytokines repressed cortisol signaling and adipogenesis. Together, these findings demonstrate the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease.

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Little is known about what regulates the homeostatic functions of fibroblasts. Here, we perform RNA sequencing and identify a gene expression program in healthy synovial fibroblasts characterized by enhanced fatty acid metabolism and lipid transport. We identify cortisol as the key driver of the healthy fibroblast phenotype and that depletion of adipocytes, which express high levels of Hsd11b1 , results in loss of the healthy fibroblast phenotype in mouse synovium. Additionally, fibroblast-specific glucocorticoid receptor Nr3c1 deletion in vivo leads to worsened arthritis. Cortisol signaling in fibroblasts mitigates matrix remodeling induced by TNF and TGF-β1 in vitro, while stimulation with these cytokines represses cortisol signaling and adipogenesis. Together, these findings demonstrate the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease. Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Here, Faust et al. find that healthy human synovial fibroblasts under the influence of adjacent adipocytes have altered lipid metabolism driven by cortisol signaling. Both adipocytes and these characteristics are lost in inflammatory arthritis.

Abstract Alternative RNA splicing results in multiple transcripts of the same gene, possibly encoding for different protein isoforms with different protein domains and functionalities. Whereas it is possible to manually determine the effect of a specific alternative splicing event on the domain composition of a particular encoded protein, the process requires the tedious integration of several data sources; it is therefore error prone and its implementation is not feasible for genome-wide characterization of domains affected by differential splicing. To fulfill the need for an automated solution, we developed the Domain Change Presenter (DoChaP), a web server for the visualization of the exon–domain association. DoChaP visualizes all transcripts of a given gene, the domains of the proteins that they encode, and the exons encoding each domain. The visualization enables a comparison between the transcripts and between the protein isoforms they encode for. The organization and visual presentation of the information makes the structural effect of each alternative splicing event on the protein structure easily identified. To enable a study of the conservation of the exon structure, alternative splicing, and the effect of alternative splicing on protein domains, DoChaP also facilitates an inter-species comparison of domain–exon associations. DoChaP thus provides a unique and easy-to-use visualization of the exon–domain association and its conservation between transcripts and orthologous genes and will facilitate the study of the functional effects of alternative splicing in health and disease. Competing Interest Statement The authors have declared no competing interest.

Animal cytokinesis ends with the formation of a thin intercellular membrane bridge connecting the two newly formed sibling cells that is ultimately resolved by abscission. While mitosis is completed within 15 minutes, the intercellular bridge can persist for hours, maintaining a physical connection between sibling cells and allowing exchange of cytosolic components. Although cell-cell communication is fundamental for development, the potential role of intercellular bridges during embryogenesis have not been fully elucidated. Here, we found that in early zebrafish (Danio rerio) embryogenesis, abscission is delayed and cells do not resolve their intercellular bridges until midblastula transition (MBT), giving rise to the formation of small inter-connected cell clusters. Interestingly, abscission commences during the MBT switch, which is manifested by cell cycle elongation, loss of synchronized divisions and genome activation. Moreover, depletion of Chmp4bb which is an essential ESCRT-III component for scission, delayed abscission beyond the MBT switch. Hallmark features of MBT, including transcription onset and cell shape changes, were similar in sibling cells connected by intercellular bridges, proposing a role for intercellular bridges in maintaining cell-cell communication in the embryo. Taken together, our data suggest that abscission is part of the cellular changes that occur during MBT and that cells coordinate their behavior during this critical embryonic phase through persisted intercellular bridges. Competing Interest Statement The authors have declared no competing interest.