Flotillin-2 dampens T cell antigen sensitivity and functionality.

T cell receptor (TCR) engagement triggers T cell responses, yet how TCR-mediated activation is regulated at the plasma membrane remains unclear. Here, we report that deleting the membrane scaffolding protein Flotillin-2 (Flot2) increases T cell antigen sensitivity, resulting in enhanced TCR signaling and effector function in response to weak TCR stimulation. T cell-specific Flot2-deficient mice exhibited reduced tumor growth and enhanced immunity to infection.

CD9 and Aryl Hydrocarbon Receptor Are Markers of Human CD19+CD14+ Atypical B Cells and Are Dysregulated in Systemic Lupus Erythematous Disease.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose expression regulates immune cell differentiation. Single-cell transcriptomic profiling was used to ascertain the heterogeneity of AHR expression in human B cell subpopulations. We identified a unique population of B cells marked by expression of AHR, CD9, and myeloid genes such as CD14 and CXCL8.

GM-CSF-dependent CD301b+ lung dendritic cells confer tolerance to inhaled allergens.

The severity of allergic asthma is driven by the balance between allergen-specific T regulatory (Treg) and T helper (Th)2 cells. However, it is unclear whether specific subsets of conventional dendritic cells (cDCs) promote the differentiation of these two T cell lineaeges. We have identified a subset of lung resident type 2 cDCs (cDC2s) that display high levels of CD301b and have potent Treg-inducing activity .

DNASE1L3 enhances antitumor immunity and suppresses tumor progression in colon cancer.

DNASE1L3, an enzyme highly expressed in DCs, is functionally important for regulating autoimmune responses to self-DNA and chromatin. Deficiency of DNASE1L3 leads to development of autoimmune diseases in both humans and mice. However, despite the well-established causal relationship between DNASE1L3 and immunity, little is known about the involvement of DNASE1L3 in regulation of antitumor immunity, the foundation of modern antitumor immunotherapy.

25-Hydroxycholesterol exacerbates vascular leak during acute lung injury.

Cholesterol-25-hydroxylase (CH25H), the biosynthetic enzyme for 25-hydroxycholesterol (25HC), is most highly expressed in the lung, but its role in lung biology is poorly defined. Recently, we reported that Ch25h is induced in monocyte-derived macrophages recruited to the airspace during resolution of lung inflammation and that 25HC promotes liver X receptor-dependent (LXR-dependent) clearance of apoptotic neutrophils by these cells. Ch25h and 25HC are, however, also robustly induced by lung-resident cells during the early hours of lung inflammation, suggesting additional cellular sources and targets.

CD11b lung dendritic cells at different stages of maturation induce Th17 or Th2 differentiation.

Dendritic cells (DC) in the lung that induce Th17 differentiation remain incompletely understood, in part because conventional CD11b DCs (cDC2) are heterogeneous. Here, we report a population of cDCs that rapidly accumulates in lungs of mice following house dust extract inhalation. These cells are Ly-6C, are developmentally and phenotypically similar to cDC2, and strongly promote Th17 differentiation ex vivo.

Effects of rosuvastatin on the immune system in healthy volunteers with normal serum cholesterol.

BACKGROUNDHMG-CoA reductase inhibitors (statins) are prescribed to millions of people. Statins are antiinflammatory independent of their cholesterol-reducing effects. To date, most reports on the immune effects of statins have assayed a narrow array of variables and have focused on cell lines, rodent models, or patient cohorts.

Contributions of nonhematopoietic cells and mediators to immune responses: implications for immunotoxicology.

Immunotoxicology assessments have historically focused on the effects that xenobiotics exhibit directly on immune cells. These studies are invaluable as they identify immune cell targets and help characterize mechanisms and/or adverse outcome pathways of xenobiotics within the immune system. However, leukocytes can receive environmental cues by cell-cell contact or via released mediators from cells of organs outside of the immune system.

mTOR and metabolic regulation of conventional and regulatory T cells.

mTOR signaling links bioenergetic and biosynthetic metabolism to immune responses. mTOR is activated by diverse upstream stimuli, including immune signals, growth factors, and nutrients. Recent studies highlight crucial roles of mTOR signaling in immune functions mediated by conventional T cells and T In this review, we discuss the regulation of mTOR signaling in T cells and the functional impacts of mTOR and metabolic pathways on T cell-mediated immune responses, with a particular focus on the differentiation and function of T.

Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs.

Memory CD8(+) T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR.

Genetic dissection of dendritic cell homeostasis and function: lessons from cell type-specific gene ablation.

Dendritic cells (DCs) are a heterogeneous cell population of great importance in the immune system. The emergence of new genetic technology utilizing the CD11c promoter and Cre recombinase has facilitated the dissection of functional significance and molecular regulation of DCs in immune responses and homeostasis in vivo. For the first time, this strategy allows observation of the effects of DC-specific gene deletion on immune system function in an intact organism.

T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming.

Naive T cells respond to antigen stimulation by exiting from quiescence and initiating clonal expansion and functional differentiation, but the control mechanism is elusive. Here we describe that Raptor-mTORC1-dependent metabolic reprogramming is a central determinant of this transitional process. Loss of Raptor abrogated T cell priming and T helper 2 (Th2) cell differentiation, although Raptor function is less important for continuous proliferation of actively cycling cells.

Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice.

Cannabidiol (CBD) is a plant-derived cannabinoid that has been predominantly characterized as anti-inflammatory. However, it is clear that immune effects of cannabinoids can vary with cannabinoid concentration, or type or magnitude of immune stimulus. The present studies demonstrate that oral administration of CBD enhanced lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice.

Δ9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2.

Δ(9)-tetrahydrocannabinol (Δ(9)-THC) has potent immune modulatory properties and can impair pathogen-induced immune defenses, which in part have been attributed to ligation of the cannabinoid receptors 1 (CB(1)) and 2 (CB(2)). Most recently, dendritic cells (DC) were identified for their potential to enhance influenza-induced immunopathology in mice lacking CB(1) and CB(2) (CB(1) (-/-)CB(2) (-/-)). This study focused on the modulation of the inflammatory immune response to influenza by Δ(9)-THC and the role of CB(1) and/or CB(2) as receptor targets for Δ(9)-THC.

Deletion of cannabinoid receptors 1 and 2 exacerbates APC function to increase inflammation and cellular immunity during influenza infection.

We and others have reported that simultaneous targeted deletion of CB(1) and CB(2) resulted in exacerbation of immune reactivity, suggesting a role of endocannabinoids in down-regulating immune function. In this study, we demonstrate that APC function is enhanced specifically in the absence of CB(1) and CB(2) signaling, resulting in an exacerbated immune response phenotype. After influenza infection, CB(1)(-/-)CB(2)(-/-) mice showed more pronounced pulmonary damage, increased inflammatory cell infiltrate, inflammation, and a greater cellular immune responses compared with WT mice, as evidenced by transcriptome analysis, more robust T cell activation, and effector cell cytokine production.

Δ9-tetrahydrocannabinol suppresses cytotoxic T lymphocyte function independent of CB1 and CB 2, disrupting early activation events.

Previously, CD8(+) T cells were found to be a sensitive target for suppression by Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in a murine model of influenza infection. To study the effect of Δ(9)-THC on CD8(+) cytotoxic T lymphocytes (CTL), an allogeneic model of MHC I mismatch was used to elicit CTL. In addition, to determine the requirement for the cannabinoid receptors 1 (CB(1)) and 2 (CB(2)) in Δ(9)-THC-mediated CTL response modulation, mice null for both receptors were used (CB(1) (-/-)CB(2) (-/-)).

The effects of targeted deletion of cannabinoid receptors CB1 and CB2 on intranasal sensitization and challenge with adjuvant-free ovalbumin.

The mechanisms by which cannabinoid receptors CB(1) and CB(2) modulate immune function are not fully elucidated. Critical tools for the determination of the role of both receptors in the immune system are CB(1)/CB(2) double null mice (CB(1)/CB(2) null), and previous studies have shown that CB(1)/CB(2) null mice exhibit exaggerated responses to various immunological stimuli. The objective of these studies was to determine the magnitude to which CB(1)/CB(2) null mice responded to the respiratory allergen ovalbumin (OVA) as compared with wild-type C57BL/6 mice.

Effects of targeted deletion of cannabinoid receptors CB1 and CB2 on immune competence and sensitivity to immune modulation by Delta9-tetrahydrocannabinol.

The role of cannabinoid receptors, CB1 and CB2, in immune competence and modulation by Delta9-tetrahydrocannabinol (Delta9-THC) was investigated in CB1(-/-)/CB2(-/-) mice. Immunofluorescence analysis of splenic leukocytes showed no significant differences in the percentage of T cell subsets, B cells, or macrophages between wild-type and CB1(-/-)/CB2(-/-) mice. Lymphoproliferative control responses to PHA, phorbol ester plus ionomycin, or LPS and sensitivity to suppression by Delta9-THC showed no profound differences between the two genotypes, although some differences were observed in control baseline responses.

Targeted deletion of cannabinoid receptors CB1 and CB2 produced enhanced inflammatory responses to influenza A/PR/8/34 in the absence and presence of Delta9-tetrahydrocannabinol.

We have previously reported that Delta-9-tetrahydrocannabinol (Delta(9)-THC)-treated mice challenged with influenza virus A/PR/8/34 (PR8) developed increased viral hemagglutinin 1 (H1) mRNA levels and decreased monocyte and lymphocyte recruitment to the pulmonary airways when compared with mice challenged with PR8 alone. The objective of the present study was to examine the role of cannabinoid (CB(1)/CB(2)) receptors in mediating the effects of Delta(9)-THC on immune and epithelial cell responses to PR8. In the current study, Delta(9)-THC-treated CB(1)/CB(2) receptor null (CB(1)-/-/CB(2)-/-) and wild-type mice infected with PR8 had marked increases in viral H1 mRNA when compared with CB(1)-/-/CB(2)-/- and wild-type mice challenged with PR8 alone.

Modulation of airway responses to influenza A/PR/8/34 by Delta9-tetrahydrocannabinol in C57BL/6 mice.

Delta(9)-tetrahydrocannabinol (Delta(9)-THC) has been widely established as a modulator of host immune responses. Accordingly, the objective of the present study was to examine the effects of Delta(9)-THC on the immune response within the lungs and associated changes in the morphology of the bronchiolar epithelium after one challenge with a nonlethal dose of the influenza virus A/PR/8 (PR8). C57BL/6 mice were treated by oral gavage with Delta(9)-THC and/or vehicle (corn oil) for 5 consecutive days.