Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
2,688
result(s) for
"Hall, Jason A"
Sort by:
Compartmentalized Control of Skin Immunity by Resident Commensals
Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease.
Journal Article
DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions
T helper 17 (T
H
17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORγt partner that coordinates transcription of selective T
H
17 genes, and is required for T
H
17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA),
Rmrp
, which is mutated in patients with cartilage-hair hypoplasia. A targeted
Rmrp
gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5–RORγt interaction and RORγt target gene transcription. Elucidation of the link between
Rmrp
and the DDX5–RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in T
H
17-dependent diseases.
The ability of the DEAD-box RNA helicase DDX5 to interact with master transcription factor RORγt is dependent on binding of the long noncoding RNA
Rmrp
; the DDX5–RORγt complex coordinates transcription of selective T
H
17 genes and is required for the pathogenicity of T
H
17 cells.
Modifiers of T
H
17 cell pathogenicity
The ability of the DEAD-box RNA helicase DDX5 to interact with master transcription factor RORγt is shown to be dependent on binding of the long noncoding RNA
Rmrp
. The DDX5–RORγt complex coordinates transcription of selective T-helper 17 (T
H
17) genes, and is required for the pathogenicity of T
H
17 lymphocytes. The discovery of this relationship between an RNA helicase and a long noncoding RNA in complex provide new insight into the role of transcriptional regulation and suggests new avenues for research into T
H
17-dependent diseases.
Journal Article
The Tec kinase ITK is essential for ILC2 survival and epithelial integrity in the intestine
Innate lymphoid cells (ILC) are lymphocytes that lack an antigen-specific receptor and are preferentially localized in non-lymphoid tissues, such as mucosal barriers. In these locations ILC respond to tissue perturbations by producing factors that promote tissue repair and improve barrier integrity. We show that mice lacking the Tec kinase ITK have impaired intestinal tissue integrity, and a reduced ability to restore homeostasis after tissue damage. This defect is associated with a substantial loss of Type 2 ILC (ILC2) in the intestinal lamina propria. Adoptive transfer of bone marrow ILC2 precursors confirms a cell-intrinsic role for ITK. Intestinal ILC2 numbers in
Itk
-/-
mice are restored by the administration of IL-2 complexes, also leading to improved intestinal tissue damage repair. Reduced Bcl-2 expression in intestinal
Itk
-/-
ILC2 is also restored to WT levels after IL-2 complex treatment, indicating a tissue-specific role for ITK in ILC2 survival in the intestine.
Signals mediating tissue-specific control of immune cell fate and function remain largely uncharacterized. Here the authors uncover a requirement of ITK, a kinase mediating TCR signaling, for IL-2-dependent ILC2 cell survival specifically in the intestine.
Journal Article
pivotal twin histidines and aromatic triad of the Escherichia coli ammonium channel AmtB can be replaced
In Escherichia coli, each subunit of the trimeric channel protein AmtB carries a hydrophobic pore for transport of NHâ⺠across the cytoplasmic membrane. Positioned along this substrate conduction pathway are two conserved elements--a pair of hydrogen-bonded histidines (H168/H318) located within the pore itself and a set of aromatic residues (F107/W148/F215) at its periplasmic entrance--thought to be critical to AmtB function. Using site-directed mutagenesis and suppressor genetics, we examined the requirement for these elements in NHâ⺠transport. This analysis shows that AmtB can accommodate, by either direct substitution or suppressor generation, acidic residues at one or both positions of the H168/H318 twin-histidine site while retaining near wild-type activity. Similarly, study of the F107/W148/F215 triad indicates that good-to-excellent AmtB function is preserved upon individual and simultaneous replacement of these aromatic amino acids with aliphatic residues. Our findings lead us to conclude that these elements and their component parts are not required for AmtB function, but instead serve to optimize its performance.
Journal Article
GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice
Tregs not only keep immune responses to autoantigens in check, but also restrain those directed toward pathogens and the commensal microbiota. Control of peripheral immune homeostasis by Tregs relies on their capacity to accumulate at inflamed sites and appropriately adapt to their local environment. To date, the factors involved in the control of these aspects of Treg physiology remain poorly understood. Here, we show that the canonical Th2 transcription factor GATA3 is selectively expressed in Tregs residing in barrier sites including the gastrointestinal tract and the skin. GATA3 expression in both murine and human Tregs was induced upon TCR and IL-2 stimulation. Although GATA3 was not required to sustain Treg homeostasis and function at steady state, GATA3 played a cardinal role in Treg physiology during inflammation. Indeed, the intrinsic expression of GATA3 by Tregs was required for their ability to accumulate at inflamed sites and to maintain high levels of Foxp3 expression in various polarized or inflammatory settings. Furthermore, our data indicate that GATA3 limits Treg polarization toward an effector T cell phenotype and acquisition of effector cytokines in inflamed tissues. Overall, our work reveals what we believe to be a new facet in the complex role of GATA3 in T cells and highlights what may be a fundamental role in controlling Treg physiology during inflammation.
Journal Article
Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling
Development of mice with hepatocyte knockout of lanosterol 14α-demethylase (H
Cyp51
−/−
) from cholesterol synthesis is characterized by the progressive onset of liver injury with ductular reaction and fibrosis. These changes begin during puberty and are generally more aggravated in the knockout females. However, a subgroup of (pre)pubertal knockout mice (runts) exhibits a pronounced male prevalent liver dysfunction characterized by downregulated amino acid metabolism and elevated
Casp12.
RORC transcriptional activity is diminished in livers of all runt mice, in correlation with the depletion of potential RORC ligands subsequent to CYP51 disruption. Further evidence for this comes from the global analysis that identified a crucial overlap between hepatic
Cyp51
−/−
and
Rorc
−/−
expression profiles. Additionally, the reduction in RORA and RORC transcriptional activity was greater in adult H
Cyp51
−/−
females than males, which correlates well with their downregulated amino and fatty acid metabolism. Overall, we identify a global and sex-dependent transcriptional de-regulation due to the block in cholesterol synthesis during development of the
Cyp51
knockout mice and provide
in vivo
evidence that sterol intermediates downstream of lanosterol may regulate the hepatic RORC activity.
Journal Article
Retraction Note: DDX5 and its associated lncRNA Rmrp modulate T.sub.H17 cell effector functions
Change History: This Article has been retracted; see accompanying Retraction. Corrected online 20 January: In this Article, author Frank Rigo was incorrectly listed with a middle initial; this has been corrected in the online versions of the paper.
Journal Article
Retraction Note: DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions
Change History: This Article has been retracted; see accompanying Retraction.
Corrected online 20 January:
In this Article, author Frank Rigo was incorrectly listed with a middle initial; this has been corrected in the online versions of the paper.
Journal Article