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TREX1 is an endoplasmic reticulum (ER)-associated negative regulator of innate immunity. TREX1 mutations are associated with autoimmune and autoinflammatory diseases. Biallelic mutations abrogating DNase activity cause autoimmunity by allowing immunogenic self-DNA to accumulate, but it is unknown how dominant frameshift (fs) mutations that encode DNase-active but mislocalized proteins cause disease...
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a crucial cytokine produced by auto-reactive T helper (Th) cells that initiate tissue inflammation. Multiple cell types can sense GM-CSF, but the identity of the pathogenic GM-CSF-responsive cells is unclear. By using conditional gene targeting, we systematically deleted the GM-CSF receptor (Csf2rb) in specific subpopulations...
Interleukin-17 (IL-17) induces pathology in autoimmunity and infections; therefore, constraint of this pathway is an essential component of its regulation. We demonstrate that the signaling intermediate MCPIP1 (also termed Regnase-1, encoded by Zc3h12a) is a feedback inhibitor of IL-17 receptor signal transduction. MCPIP1 knockdown enhanced IL-17-mediated signaling, requiring MCPIP1’s endoribonuclease...
Three subsets of invariant natural killer T (iNKT) cells have been identified, NKT1, NKT2, and NKT17, which produce distinct cytokines when stimulated, but little is known about their localization. Here, we have defined the anatomic localization and systemic distribution of these subsets and measured their cytokine production. Thymic NKT2 cells that produced interleukin-4 (IL-4) at steady state were...
Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat containing (NLRP3) inflammasome, which might stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill...
Immunoglobulin A (IgA) is prominently secreted at mucosal surfaces and coats a fraction of the intestinal microbiota. However, the commensal bacteria bound by IgA are poorly characterized and the type of humoral immunity they elicit remains elusive. We used bacterial flow cytometry coupled with 16S rRNA gene sequencing (IgA-Seq) in murine models of immunodeficiency to identify IgA-bound bacteria and...
CD8+ T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8+ T cell response, with limited bystander activation of non-HIV memory CD8+ T cells. HIV-specific CD8+ T cells...
The immune response requires major changes to metabolic processes, and indeed, energy metabolism and functional activation are fully integrated in immune cells to determine their ability to divide, differentiate, and carry out effector functions. Immune cell metabolism has therefore become an attractive target area for therapeutic purposes. A neglected aspect in the translation of immunometabolism...
Many functionally important interactions between genes and proteins involved in immunological diseases and processes are unknown. The exponential growth in public high-throughput data offers an opportunity to expand this knowledge. To unlock human-immunology-relevant insight contained in the global biomedical research effort, including all public high-throughput datasets, we performed immunological-pathway-focused...
Innate resistance to Candida albicans in mucosal tissues requires the production of interleukin-17A (IL-17A) by tissue-resident cells early during infection, but the mechanism of cytokine production has not been precisely defined. In the skin, we found that dermal γδ T cells were the dominant source of IL-17A during C. albicans infection and were required for pathogen resistance. Induction of IL-17A...
Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically engineered mouse model of lung adenocarcinoma and found that Treg cells suppressed anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLSs)....
TREX1 regulates innate immune responses by counteracting DNA accumulation in the cytosol. In this issue of Immunity, Hasan et al. (2015) show that TREX1 also safeguards the cell against free glycan build-up in the endoplasmic reticulum, thereby preventing glycan-induced inflammation.
Bacterial infection induces inflammasome activation and release of interleukin-1 (IL-1) cytokines. Bronner et al. (2015) show that during Brucella abortus infection, an endoplasmic reticulum stress sensor, IRE1α, initiates NLRP3- and caspase-2-mediated mitochondrial damage that potentiates NLRP3 inflammasome assembly.
Immune cells play a key role in host defense against infection and cancer. Upon encountering danger signals, these cells undergo activation leading to a modulation in their immune functions. However, recent studies reveal that immune cells upon activation also show distinct metabolic changes that impact their immune functions. Such metabolic reprogramming and its functional effects are well known...
Sensory neurons are important in controlling cutaneous inflammation, but the role of neurons in host antimicrobial defense was relatively unknown. Kaplan and colleagues now demonstrate that nociceptive fibers within the dermis play a crucial role in antifungal defenses through their influence on dermal dendritic cells and induction of IL-17A.
The intestinal epithelial barrier plays a critical role in the mucosal immunity. However, it remains largely unknown how the epithelial barrier is maintained after damage. Here we show that growth factor FGF2 synergized with interleukin-17 (IL-17) to induce genes for repairing of damaged epithelium. FGF2 or IL-17 deficiency resulted in impaired epithelial proliferation, increased pro-inflammatory...
IgA is induced through T-cell-dependent and -independent pathways. In this issue, Bunker et al. (2015) now show that the T-cell-independent pathway is sufficient to coat most small intestinal microbes specifically, and Fransen et al. (2015) find that IgA coating promotes uptake of microbes into Peyer’s patches and drives further induction in a positive-feedback loop.
Elucidating the function of tumor-infiltrating regulatory T (Treg) cells has been difficult. In this issue of Immunity, Joshi et al. (2015) demonstrate that Treg cells associated with murine lung cancers are found within tertiary lymphoid structures and actively restrain effector T cells at the tumor site.
The interrelationship between IgAs and microbiota diversity is still unclear. Here we show that BALB/c mice had higher abundance and diversity of IgAs than C57BL/6 mice and that this correlated with increased microbiota diversity. We show that polyreactive IgAs mediated the entrance of non-invasive bacteria to Peyer’s patches, independently of CX3CR1+ phagocytes. This allowed the induction of bacteria-specific...
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