As shown by analysis of mice and humans bearing DOCK8-inactivating mutations, DOCK8 plays a cell-autonomous role in survival of naive CD8 T cells, LFA-1 polarization toward the immune synapse, and CD8 T cell memory and recall responses following viral infection.

Increasing evidence has challenged the traditional view about the immune privilege of the brain, but the precise roles of immune cells in regulating brain physiology and function remain poorly understood. Here, we report that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the choroid plexus of aged brains. ILC2 in the aged brain are long-lived, are relatively resistant to cellular senescence and exhaustion, and are capable of switching between cell cycle dormancy and proliferation. They are functionally quiescent at homeostasis but can be activated by IL-33 to produce large amounts of type 2 cytokines and other effector molecules in vitro and in vivo. Intracerebroventricular transfer of activated ILC2 revitalized the aged brain and enhanced the cognitive function of aged mice. Administration of IL-5, a major ILC2 product, was sufficient to repress aging-associated neuroinflammation and alleviate aging-associated cognitive decline. Targeting ILC2 in the aged brain may provide new avenues to combat aging-associated neurodegenerative disorders.

Despite mounting evidence suggesting the involvement of the immune system in regulating brain function, the specific role of immune and inflammatory cells in neurodegenerative diseases remain poorly understood. In this study, we report that depletion of NK cells, a type of innate lymphocytes, alleviates neuroinflammation, stimulates neurogenesis, and improves cognitive function in a triple-transgenic Alzheimer disease (AD) mouse model. NK cells in the brains of triple-transgenic AD mouse model (3xTg-AD) mice exhibited an enhanced proinflammatory profile. Depletion of NK cells by anti-NK1.1 Abs drastically improved cognitive function of 3xTg-AD mice. NK cell depletion did not affect amyloid b concentrations but enhanced neurogenesis and reduced neuroinflammation. Notably, in 3xTg-AD mice depleted of NK cells, microglia demonstrated a homeostatic-like morphology, decreased proliferative response and reduced expression of neurodestructive proinflammatory cytokines. Together, our results suggest a proinflammatory role for NK cells in 3xTg-AD mice and indicate that targeting NK cells might unlock novel strategies to combat AD.

The effects of aging on innate immunity and the resulting impacts on immunosenescence remain poorly understood. Here, we report that aging induces compartmentalized changes to the development and function of group 2 innate lymphoid cells (ILC2), an ILC subset implicated in pulmonary homeostasis and tissue repair. Aging enhances bone marrow early ILC2 development through Notch signaling, but the newly generated circulating ILC2 are unable to settle in the lungs to replenish the concomitantly declining mature lung ILC2 pool in aged mice. Aged lung ILC2 are transcriptomically heterogeneous and functionally compromised, failing to produce cytokines at homeostasis and during influenza infection. They have reduced expression of Cyp2e1, a cytochrome P450 oxidase required for optimal ILC2 function. Transfer of lung ILC2 from young mice enhances resistance to influenza infection in old mice. These data highlight compartmentalized effects of aging on ILC and indicate that targeting tissue‐resident ILCs might unlock therapies to enhance resistance to infections and diseases in the elderly.

Background: Asthma is a complicated chronic inflammatory disorder characterized by airway inflammation and bronchial hyperresponsiveness. Group 2 innate lymphoid cells (ILC2) are tissue-resident innate effector cells that can mediate airway inflammation and hyperresponsiveness through production of IL-5, IL-13 and VEGFA. ILC2 in asthma patients exhibit an activated phenotype. However, molecular pathways that control ILC2 activation are not well understood.Methods: MYC expression was examined in ILC2 sorted from peripheral blood of healthy controls and asthma patients or cultured with or without activating cytokines. CRISPR knockout technique was used to delete c-Myc in primary murine lung ILC2 or an ILC2 cell line. Cell proliferation was examined, gene expression pattern was profiled by genome-wide microarray analysis, and direct gene targets were identified by Chromatin immunoprecipitation (ChIP). ILC2 responses, airway inflammation and airway hyperresponsiveness were examined in Balb/c mice challenged with Alternaria extracts, with or without treatment with JQ1. Results: ILC2 from asthma patients expressed increased amounts of MYC. Deletion of c-Myc in ILC2 results in reduced proliferation, decreased cytokine production, and reduced expression of many lymphocyte activation genes. ChIP identified Stat6 as a direct gene target of c-Myc in ILC2. In vivo inhibition of c-Myc by JQ1 treatment repressed ILC2 activity and suppressed Alternaria-induced airway inflammation and AHR. Conclusion: c-Myc expression is upregulated during ILC2 activation. c-Myc is essential for ILC2 activation and their in vivo pathogenic effects. These findings suggest that targeting c-Myc may unlock novel strategies to combat asthma or asthma exacerbation. K E Y W O R D S airway hyperresponsiveness, asthma, c-Myc, ILC2 S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Ye L, Pan J, Liang M, et al. A critical role for c-Myc in group 2 innate lymphoid cell activation. Allergy. 2020;75:841-852. https ://doi.

The microarray data presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo) under accession number GSE116062.

Asthma is a complicated chronic airway inflammatory disorder.In addition to standard steroid treatment, biologic therapies targeting specific cytokines have emerged to reduce exacerbation and improve lung function. Neutralizing antibodies against IL-5, a critical growth factor for eosinophils, reduced asthma exacerbation in patients with severe eosinophilic asthma. 1 Blockade of IL4Rα, the receptor to IL-4 and IL-13, also lowered exacerbation rates and improved lung function in moderate to severe uncontrolled asthma. 2 While these biologic therapies are now used as add-on maintenance treatment of moderate to severe asthma, the effects of these biologic therapies on human immune responses are yet to be better understood.Recent work from us and others has indicated critical roles for group-2 innate lymphoid cells (ILC2), a type of lung-resident innate effector cells, in asthma pathogenesis. 3-5 ILC2 may mediate airway inflammation and hyperresponsiveness through production of IL-5, IL-13 and VEGFA. 5,6 They may also enhance Th2 responses by expression of MHCII and co-stimulating factors. 7 How human ILC2 may respond to biologic therapies remains unclear. A recent study demonstrates that human ILC2 do not express IL-5R, indicating that human ILC2 are unlikely to directly respond to anti-IL-5 therapy. 8Nevertheless, previous work with mouse models suggest that IL-4 might promote cytokine production activity of mouse ILC2, through direct interaction with IL-4Rα 9 However, whether and how human ILC2 may respond to IL-4 remain unknown.We hypothesize that IL-4/IL-4Rα signalling may promote human ILC2 response through both autocrine and endocrine regulation and that blockade of IL-4Rα by dupilumab can repress pathogenic ILC2 responses in asthma patients.To examine human ILC2 function, we isolated human blood ILC2 by fluorescence-activated cell sorting (FACS) and cultured them in vitro in the presence of IL-2, IL-7, IL-25 and IL-33. Human ILC2 were identified as CD45 + Lin -IL7Ra + CRTH2 + cells as previously described ( Figure 1A). 5 A total of 5 Χ 10 3 sorted ILC2 were cultured in 200 µL of alpha-MEDM medium supplemented with 20% FCS and 20 ng/mL IL-2, IL-7, IL-25 and IL-33 in round bottom 96-well plates. Human ILC2 produced a large amount of IL-5 and IL-13, and also intermediate levels of IL-4 in vitro ( Figure 1B). We next sought to understand whether IL-4 and/or IL-13 may control human ILC2 activity through autocrine regulation. We used neutralizing antibodies to block IL-4 and/or IL-13 activity in human ILC2 culture. Blockade of IL-4 signalling significantly repressed proliferation of human ILC2 in vitro ( Figure 1C). ELISA revealed that the production of IL-13 by human ILC2 was also greatly reduced with IL-4 blockade ( Figure 1D). Thus, IL-4 may promote human ILC2 proliferation and activation through autocrine regulation. IL-13 also acts through IL-4Rα signalling. However, neutralization of IL-13 did not affect the proliferation or the cytokine production of cultured human ILC2 ( Figure 1C,E,F). Combined treatment w...

No abstract