Stress-induced glucocorticoids enhance acute inflammation by promoting the differentiation of Th17 cells.

Stress can trigger acute inflammation by increasing the pro-inflammatory cytokine interleukin (IL)-17 for injury and infection, while inducing the production of the immunosuppressive hormone glucocorticoids (GCs). However, the mechanism through which stress-induced GCs enhance acute inflammation by directly regulating the development of IL-17-producing helper T (Th17) cells remains unclear. Here, we demonstrate that GCs promote Th17 cell differentiation and survival in both mice and humans.

IL-7Rα signaling in regulatory T cells of adipose tissue is essential for systemic glucose homeostasis.

Regulatory T cells (Tregs) mediate tissue homeostasis and repair. The function of the interleukin-7 receptor α (IL-7Rα) in nonlymphoid tissue Tregs is still unknown, although low expression of IL-7Rα is a widely accepted marker for Tregs. Here, we show that IL-33R (ST2)-expressing Tregs in the visceral adipose tissue (VAT) express the IL-7Rα at high levels.

The transcription factor RORα is required for the development of type 1 innate lymphoid cells in adult bone marrow.

Type 1 innate lymphoid cells (ILC1s) respond to infections and tumors by producing IFN-γ. Although RAR-related orphan receptor α (RORα) is required for ILC2s and some ILC3s, its role in ILC1 development remains controversial. To investigate the role of RORα in ILC1s, we analyzed bone marrow (BM) chimeras of RORα-deficient mice.

A Chimeric IL-7Rα/IL-2Rβ Receptor Promotes the Differentiation of T Cell Progenitors into B Cells and Type 2 Innate Lymphoid Cells.

IL-7 and IL-2 are evolutionarily related cytokines that play critical roles in the development and expansion of immune cells. Although both IL-7R and IL-2R activate similar signaling molecules, whether their signals have specific or overlapping functions during lymphocyte differentiation remains unclear. To address this question, we generated IL-7R α-chain (IL-7Rα)/IL-2R β-chain (IL-24β) (72R) knock-in mice expressing a chimeric receptor consisting of the extracellular domain of IL-7Rα and the intracellular domain of IL-2Rβ under the control of the endogenous IL-7Rα promoter.

γδ intraepithelial lymphocytes acquire the ability to produce IFN-γ in a different time course than αβ intraepithelial lymphocytes.

An age-dependent increase in interferon (IFN)-γ expression by intestinal intraepithelial lymphocytes (IELs) contributes to the acquisition of resistance to infection by pathogens. However, how IELs acquire the ability to produce IFN-γ remains to be elucidated. Here, we report that IELs in the small intestine acquire the ability to rapidly produce IFN-γ at two distinct life stages.

Hematopoietic cell-derived IL-15 supports NK cell development in scattered and clustered localization within the bone marrow.

Natural killer (NK) cells are innate immune cells critical for protective immune responses against infection and cancer. Although NK cells differentiate in the bone marrow (BM) in an interleukin-15 (IL-15)-dependent manner, the cellular source of IL-15 remains elusive. Using NK cell reporter mice, we show that NK cells are localized in the BM in scattered and clustered manners.

Lung group 2 innate lymphoid cells differentially depend on local IL-7 for their distribution, activation, and maintenance in innate and adaptive immunity-mediated airway inflammation.

Interleukin-7 (IL-7) is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 produced in the lung plays a role in the maintenance and function of lung ILC2s during airway inflammation remains unknown.

A circulating subset of iNKT cells mediates antitumor and antiviral immunity.

Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues.

Interleukin-7 receptor signaling is crucial for enhancer-dependent TCRδ germline transcription mediated through STAT5 recruitment.

γδ T cells play important roles in immune responses by rapidly producing large quantities of cytokines. Recently, γδ T cells have been found to be involved in tissue homeostatic regulation, playing roles in thermogenesis, bone regeneration and synaptic plasticity. Nonetheless, the mechanisms involved in γδ T-cell development, especially the regulation of TCRδ gene transcription, have not yet been clarified.

The transcription factor E2A activates multiple enhancers that drive expression in developing T and B cells.

Cell type-specific gene expression is driven by the interplay between lineage-specific transcription factors and cis-regulatory elements to which they bind. Adaptive immunity relies on RAG-mediated assembly of T cell receptor () and immunoglobulin () genes. Although and expression is largely restricted to adaptive lymphoid lineage cells, it remains unclear how gene expression is regulated in a cell lineage-specific manner.

Innate-like CD27CD45RB γδ T Cells Require TCR Signaling for Homeostasis in Peripheral Lymphoid Organs.

TCR signaling is required for homeostasis of naive αβ T cells. However, whether such a signal is necessary for γδ T cell homeostasis in the periphery remains unknown. In this study, we present evidence that a portion of Vγ2 γδ T cells, one of the major γδ T cell subsets in the secondary lymphoid organs, requires TCR signaling for homeostasis.

IL-7R-Dependent Phosphatidylinositol 3-Kinase Competes with the STAT5 Signal to Modulate T Cell Development and Homeostasis.

T cell development and homeostasis requires IL-7R α-chain (IL-7Rα) signaling. Tyrosine Y449 of the IL-7Rα is essential to activate STAT5 and PI3K, whereas PI3K recruitment requires IL-7Rα methionine M452. How IL-7Rα activates and regulates both signaling pathways differentially remains unclear.

Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intra-epithelial lymphocytes in the intestine.

Interleukin-15 (IL-15) is a cytokine critical for maintenance of intestinal intra-epithelial lymphocytes (IELs), especially CD8αα + IELs (CD8αα IELs). In the intestine, IL-15 is produced by intestinal epithelial cells (IECs), blood vascular endothelial cells (BECs) and hematopoietic cells. However, the precise role of intestinal IL-15 on IELs is still unknown.

Mesenchymal stromal cells in bone marrow express adiponectin and are efficiently targeted by an adiponectin promoter-driven Cre transgene.

Stromal cells in bone marrow (BM) constitute a specific microenvironment supporting the development and maintenance of hematopoietic cells. Adiponectin is a cytokine secreted by adipocytes. Besides its anti-diabetic and anti-atherogenic roles, adiponectin reportedly regulates the development and function of hematopoietic cells in BM.

Notch Signaling Controls Transcription via the Recruitment of RUNX1 and MYB to Enhancers during T Cell Development.

and display identical developmental programs that depend on the activity of the enhancers Eδ and Eγ being "on" in pre-β-selection thymocytes to activate transcription and V(D)J recombination of the unrearranged genes and "off" in post-β-selection CD4CD8 double-positive thymocytes to inhibit transcription of the rearranged genes and avoid the expression of TCR δ- and TCR γ-chains in αβ T lymphocytes. Eδ and Eγ activity depends on transcription factor binding to essential Runx and Myb sites and parallels that of Notch signaling. We performed Notch gain- and loss-of-function experiments and found that Notch signaling activates and transcription by favoring the recruitment of RUNX1 and MYB to the enhancers.

Glucocorticoids Drive Diurnal Oscillations in T Cell Distribution and Responses by Inducing Interleukin-7 Receptor and CXCR4.

Glucocorticoids are steroid hormones with strong anti-inflammatory and immunosuppressive effects that are produced in a diurnal fashion. Although glucocorticoids have the potential to induce interleukin-7 receptor (IL-7R) expression in T cells, whether they control T cell homeostasis and responses at physiological concentrations remains unclear. We found that glucocorticoid receptor signaling induces IL-7R expression in mouse T cells by binding to an enhancer of the IL-7Rα locus, with a peak at midnight and a trough at midday.

Hematopoietic Stem Cell Niches Produce Lineage-Instructive Signals to Control Multipotent Progenitor Differentiation.

Hematopoietic stem cells (HSCs) self-renew in bone marrow niches formed by mesenchymal progenitors and endothelial cells expressing the chemokine CXCL12, but whether a separate niche instructs multipotent progenitor (MPP) differentiation remains unclear. We show that MPPs resided in HSC niches, where they encountered lineage-instructive differentiation signals. Conditional deletion of the chemokine receptor CXCR4 in MPPs reduced differentiation into common lymphoid progenitors (CLPs), which decreased lymphopoiesis.

Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation.

Memory CD4(+) T helper (Th) cells are central to long-term protection against pathogens, but they can also be pathogenic and drive chronic inflammatory disorders. How these pathogenic memory Th cells are maintained, particularly at sites of local inflammation, remains unclear. We found that ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue (iBALT) are formed during chronic allergic inflammation in the lung, and that memory-type pathogenic Th2 (Tpath2) cells capable of driving allergic inflammation are maintained within the iBALT structures.

An Enhancer of the IL-7 Receptor α-Chain Locus Controls IL-7 Receptor Expression and Maintenance of Peripheral T Cells.

The IL-7R plays critical roles in lymphocyte development and homeostasis. Although IL-7R expression is strictly regulated during lymphocyte differentiation and the immune response, little is known regarding its in vivo regulation. To address this issue, we established a mouse line with targeted deletion of the conserved non-coding sequence 1 (CNS1) element found 3.

STAT5 Orchestrates Local Epigenetic Changes for Chromatin Accessibility and Rearrangements by Direct Binding to the TCRγ Locus.

The transcription factor STAT5, which is activated by IL-7R, controls chromatin accessibility and rearrangements of the TCRγ locus. Although STAT-binding motifs are conserved in Jγ promoters and Eγ enhancers, little is known about their precise roles in rearrangements of the TCRγ locus in vivo. To address this question, we established two lines of Jγ1 promoter mutant mice: one harboring a deletion in the Jγ1 promoter, including three STAT motifs (Jγ1P(Δ/Δ)), and the other carrying point mutations in the three STAT motifs in that promoter (Jγ1P(mS/mS)).

Reprint of: Environments of B cell development.

B lymphocyte development in the mouse begins with the generation of long-term reconstituting, pluripotent hematopoietic stem cells, over multipotent myeloid/lymphoid progenitors and common lymphoid progenitors to B-lineage committed pro/pre B and pre B cells, which first express pre B cell receptors and then immunoglobulins, B cell receptors, to generate the repertoires of peripheral B cells. This development is influenced and guided by cells of non-hematopoietic and hematopoietic origins. We review here some of the recent developments, and our contributions in this fascinating field of developmental immunology.

Characterization of the IL-15 niche in primary and secondary lymphoid organs in vivo.

IL-15 is a cytokine critical for development, maintenance, and response of T cells, natural killer (NK) cells, NK T cells, and dendritic cells. However, the identity and distribution of IL-15-expressing cells in lymphoid organs are not well understood. To address these questions, we established and analyzed IL-15-CFP knock-in mice.