Person: Glimcher, Laurie
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Glimcher
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Laurie
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Glimcher, Laurie
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Publication A multiple redundant genetic switch locks in the transcriptional signature of T regulatory cells(2013) Fu, Wenxian; Ergun, Ayla; Lu, Ting; Hill, Jonathan A.; Haxhinasto, Sokol; Fassett, Marlys S.; Gazit, Roi; Adoro, Stanley; Glimcher, Laurie; Chan, Susan; Kastner, Philippe; Rossi, Derrick; Collins, James J.; Mathis, Diane; Benoist, ChristopheThe transcription factor FoxP3 partakes dominantly in the specification and function of FoxP3+CD4+ T regulatory cells (Tregs), but is neither strictly necessary nor sufficient to determine the characteristic Treg signature. Computational network inference and experimental testing assessed the contribution of other transcription factors (TF). Enforced expression of Helios or Xbp1 elicited specific signatures, but Eos, Irf4, Satb1, Lef1 and Gata1 elicited exactly the same outcome, synergizing with FoxP3 to activate most of the Treg signature, including key TFs, and enhancing FoxP3 occupancy at its genomic targets. Conversely, the Treg signature was robust to inactivation of any single cofactor. A redundant genetic switch thus locks-in the Treg phenotype, a model which accounts for several aspects of Treg physiology, differentiation and stability.Publication An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease(American Association for the Advancement of Science (AAAS), 2015-08-12) Zhang, Sufeng; Ermann, Joerg; Succi, Marc; Zhou, Allen; Hamilton, Matthew; Cao, Bonnie; Korzenik, Joshua; Glickman, Jonathan; Vemula, Praveen K.; Glimcher, Laurie; Traverso, Giovanni; Langer, Robert; Karp, JeffreyA hydrogel binds to inflamed tissues, delivering therapeutics locally and reducing systemic drug exposure in mouse models of inflammatory bowel disease.Publication Bifidobacterium animalis subsp. lactis fermented milk product reduces inflammation by altering a niche for colitogenic microbes(Proceedings of the National Academy of Sciences, 2010) Veiga, Patrick; Gallini, Carey; Beal, C.; Michaud, Monia; Delaney, Mary; DuBois, A.; Khlebnikov, A.; van Hylckama Vlieg, J. E. T.; Punit, S.; Glickman, Jonathan; Onderdonk, Andrew; Glimcher, Laurie; Garrett, WendyIntestinal health requires the coexistence of eukaryotic self with the gut microbiota and dysregulated host-microbial interactions can result in intestinal inflammation. Here, we show that colitis improved in T-bet(-/-)Rag2(-/-) mice that consumed a fermented milk product containing Bifidobacterium animalis subsp. lactis DN-173 010 strain. A decrease in cecal pH and alterations in short chain fatty acid profiles occurred with consumption, and there were concomitant increases in the abundance of select lactate-consuming and butyrate-producing bacteria. These metabolic shifts created a nonpermissive environment for the Enterobacteriaceae recently identified as colitogenic in a T-bet(-/-)Rag2(-/-) ulcerative colitis mouse model. In addition, 16S rRNA-based analysis of the T-bet(-/-)Rag2(-/-) fecal microbiota suggest that the structure of the endogenous gut microbiota played a key role in shaping the host response to the bacterial strains studied herein. We have identified features of the gut microbiota, at the membership and functional level, associated with response to this B. lactis-containing fermented milk product, and therefore this model provides a framework for evaluating and optimizing probiotic-based functional foods.Publication NFATc1 in Mice Represses Osteoprotegerin During Osteoclastogenesis and Dissociates Systemic Osteopenia From Inflammation in Cherubism(American Society for Clinical Investigation, 2008-11-03) Aliprantis, Antonios O.; Ueki, Yasuyoshi; Sulyanto, Rosalyn; Park, Arnold; Sigrist, Kirsten S.; Sharma, Sudarshana M.; Ostrowski, Michael C.; Olsen, Bjorn; Glimcher, LaurieOsteoporosis results from an imbalance in skeletal remodeling that favors bone resorption over bone formation. Bone matrix is degraded by osteoclasts, which differentiate from myeloid precursors in response to the cytokine RANKL. To gain insight into the transcriptional regulation of bone resorption during growth and disease, we generated a conditional knockout of the transcription factor nuclear factor of activated T cells c1 (Nfatc1). Deletion of Nfatc1 in young mice resulted in osteopetrosis and inhibition of osteoclastogenesis in vivo and in vitro. Transcriptional profiling revealed NFATc1 as a master regulator of the osteoclast transcriptome, promoting the expression of numerous genes needed for bone resorption. In addition, NFATc1 directly repressed osteoclast progenitor expression of osteoprotegerin, a decoy receptor for RANKL previously thought to be an osteoblast-derived inhibitor of bone resorption. “Cherubism mice”, which carry a gain-of-function mutation in SH3-domain binding protein 2 (Sh3bp2), develop osteoporosis and widespread inflammation dependent on the proinflammatory cytokine, TNF-α. Interestingly, deletion of Nfatc1 protected cherubism mice from systemic bone loss but did not inhibit inflammation. Taken together, our study demonstrates that NFATc1 is required for remodeling of the growing and adult skeleton and suggests that NFATc1 may be an effective therapeutic target for osteoporosis associated with inflammatory states.Publication The transcription factor XBP1 is selectively required for eosinophil differentiation(Nature Publishing Group, 2015) Bettigole, Sarah Elizabeth; Lis, Raphael; Adoro, Stanley; Lee, Ann-Hwee; Spencer, Lisa; Weller, Peter; Glimcher, LaurieThe transcription factor XBP1 has been linked to the development of highly secretory tissues such as plasma cells and Paneth cells, yet its function in granulocyte maturation has remained unknown. Here we discovered an unexpectedly selective and absolute requirement for XBP1 in eosinophil differentiation without an effect on the survival of basophils or neutrophils. Progenitors of myeloid cells and eosinophils selectively activated the endoribonuclease IRE1α and spliced Xbp1 mRNA without inducing parallel endoplasmic reticulum (ER) stress signaling pathways. Without XBP1, nascent eosinophils exhibited massive defects in the post-translational maturation of key granule proteins required for survival, and these unresolvable structural defects fed back to suppress critical aspects of the transcriptional developmental program. Hence, we present evidence that granulocyte subsets can be distinguished by their differential reliance on secretory-pathway homeostasis.Publication IRE1α Activation Protects Mice Against Acetaminophen-Induced Hepatotoxicity(The Rockefeller University Press, 2012) Hur, Kyu Yeon; So, Jae-Seon; Ruda, Vera; Frank-Kamenetsky, Maria; Fitzgerald, Kevin; Koteliansky, Victor; Iwawaki, Takao; Glimcher, Laurie; Lee, Ann-HweeMice lacking the transcription factor XBP1 exhibit constitutive activation of the stress sensor IRE1α and are protected from acetaminophen overdose–induced acute liver failure.Publication The Transcription T-bet is Required for Optimal Proinflammatory Trafficking of CD4+ T Cells(BioMed Central, 2005) Rao, RM; Lord, GM; Choe, H.; Lichtman, AH; Luscinskas, FW; Glimcher, LaurieBackground: The transcription factor T-bet is a critical regulator of Th1 effector function. Animals deficient in T-bet are protected from a variety of inflammatory diseases, including systemic lupus erythematosus and inflammatory arthritis. An essential function of Th1 cells is the ability to traffic appropriately to sites of inflammation, which is largely dependent on the expression of specific selectin ligands and chemokine receptors. We therefore hypothesised that T-bet would modulate lymphocyte trafficking in vitro and in vivo by direct regulation of both selectin binding and chemokine function. Methods: Balb/c mice deficient in, or transgenic for, T-bet had been generated previously. T-bet\(^{-/-}\) × DO11.10 TCR and T-bet\(^{-/-}\) × IFN\(^{-/-}\) mice were generated by backcrossing for >10 generations. CD4\(^+\) T cells were generated from primary lymph nodes from all these mice by positive selection and stimulation with appropriate antigen. Functional analysis used the following four methods: adoptive transfer into WT Balb/c mice, which were then injected with OVA, cells were harvested from the spleen, lymph node and peritoneum; selectin binding, interactions with immoblised P-selectin and E-selectin under conditions of laminar flow were examined in a parallel plate flow chamber; expression of selectin ligands, using flow cytometry, real-time PCR and 35S incorporation; and chemokine receptor expression and function, using flow cytometry, real-time PCR, transwell chemotaxis and endothelial binding under flow conditions. Results: Selective migration of T-bet\(^{-/-}\) CD4\(^+\) T cells in a Th1-dependent model of peritoneal inflammation was completely abrogated. Further investigation revealed that this effect was due to a 50% reduction in binding to P-selectin but not E-selectin under in vitro flow conditions and that this was as a result of impaired tyrosine sulfation of PSGL-1. In addition, mRNA and surface expression of CXCR3, but not CCR5, was reduced and this was associated with a reduction in both transwell chemotaxis and binding to endothelial cells. Retroviral transfer experiments of T-bet cDNA into T-bet\(^{-/-}\) and T-bet\(^{-/-}\) × IFN\(^{-/-}\) cells demonstrated that these effects were independent of interferon. Conclusions: These data establish that T-bet imprints a specific migratory program onto developing CD4\(^+\) cells via control of PSGL-1 sulfation (and thus P-selectin binding) and CXCR3 expression and function. Furthermore, as E-selectin and CCR5 binding are unimpaired, this reveals a level of control on trafficking of Th1 lymphocytes not recognised by previous paradigms.Publication XBP1 Governs Late Events in Plasma Cell Differentiation and Is not Required for Antigen-Specific Memory B Cell Development(Rockefeller University Press, 2009) McHeyzer-Williams, Louise J.; Kowal, Czeslawa; Lee, Ann-Hwee; Volpe, Bruce T.; Diamond, Betty; McHeyzer-Williams, Michael G.; Todd, Derrick; Glimcher, LaurieThe unfolded protein response (UPR) is a stress response pathway that is driven by the increased load of unfolded proteins in the endoplasmic reticulum of highly secretory cells such as plasma cells (PCs). X box binding protein 1 (XBP1) is a transcription factor that mediates one branch of the UPR and is crucial for the development of antibody-secreting PCs. PCs represent only one class of terminally differentiated B cells, however, and little is known about the role for XBP1 in the other class: memory B cells. We have developed an XBP1fl/fl CD19+/cre conditional knockout (XBP1CD19) mouse to build upon our current understanding of the function of XBP1 in PC differentiation as well as to explore the role of XBP1 in memory cell development. Using this model, we show that XBP1CD19 mice are protected from disease in an autoantibody-mediated mouse lupus model. We also identify a novel developmental stage at which B cells express the traditional PC marker CD138 (syndecan-1) but have yet to undergo XBP1-dependent functional and morphological differentiation into antibody-secreting cells. Finally, we show that memory B cells develop normally in XBP1CD19 mice, demonstrating that XBP1-mediated functions occur independently of any memory cell lineage commitment.Publication Control of T Helper Cell Differentiation through Cytokine Receptor Inclusion in the Immunological Synapse(The Rockefeller University Press, 2009) Maldonado, Roberto A.; Soriano, Michelle A.; Perdomo, L. Carolina; Sigrist, Kirsten; Irvine, Darrell J.; Decker, Thomas; Glimcher, LaurieThe antigen recognition interface formed by T helper precursors (Thps) and antigen-presenting cells (APCs), called the immunological synapse (IS), includes receptors and signaling molecules necessary for Thp activation and differentiation. We have recently shown that recruitment of the interferon-γ receptor (IFNGR) into the IS correlates with the capacity of Thps to differentiate into Th1 effector cells, an event regulated by signaling through the functionally opposing receptor to interleukin-4 (IL4R). Here, we show that, similar to IFN-γ ligation, TCR stimuli induce the translocation of signal transducer and activator of transcription 1 (STAT1) to IFNGR1-rich regions of the membrane. Unexpectedly, STAT1 is preferentially expressed, is constitutively serine (727) phosphorylated in Thp, and is recruited to the IS and the nucleus upon TCR signaling. IL4R engagement controls this process by interfering with both STAT1 recruitment and nuclear translocation. We also show that in cells with deficient Th1 or constitutive Th2 differentiation, the IL4R is recruited to the IS. This observation suggest that the IL4R is retained outside the IS, similar to the exclusion of IFNGR from the IS during IL4R signaling. This study provides new mechanistic cues for the regulation of lineage commitment by mutual immobilization of functionally antagonistic membrane receptors.Publication TAK1 is an Essential Regulator of BMP Signalling in Cartilage(Nature Publishing Group, 2009) Shim, Jae-Hyuck; Greenblatt, Matthew Blake; Xie, Min; Schneider, Michael D; Zou, Weigou; Zhai, Bo; Gygi, Steven; Glimcher, LaurieTGFβ activated kinase 1 (TAK1), a member of the MAPKKK family, controls diverse functions ranging from innate and adaptive immune system activation to vascular development and apoptosis. To analyse the in vivo function of TAK1 in cartilage, we generated mice with a conditional deletion of Tak1 driven by the collagen 2 promoter. Tak1\(^{col2}\) mice displayed severe chondrodysplasia with runting, impaired formation of secondary centres of ossification, and joint abnormalities including elbow dislocation and tarsal fusion. This phenotype resembled that of bone morphogenetic protein receptor (BMPR)1 and Gdf5-deficient mice. BMPR signalling was markedly impaired in TAK1-deficient chondrocytes as evidenced by reduced expression of known BMP target genes as well as reduced phosphorylation of Smad1/5/8 and p38/Jnk/Erk MAP kinases. TAK1 mediates Smad1 phosphorylation at C-terminal serine residues. These findings provide the first in vivo evidence in a mammalian system that TAK1 is required for BMP signalling and functions as an upstream activating kinase for Smad1/5/8 in addition to its known role in regulating MAP kinase pathways. Our experiments reveal an essential role for TAK1 in the morphogenesis, growth, and maintenance of cartilage.