ResearchPad - 312 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways]]> https://www.researchpad.co/article/elastic_article_15296 Resident memory T cells (TRM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung TRM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial TRM cells have distinct effector functions and that CXCR6 controls the partitioning of TRM cells within the lung by recruiting CD8 TRM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 TRM cells due to altered trafficking of CXCR6−/− cells within the lung, and not decreased survival in the airways. CXCL16, the ligand for CXCR6, is localized primarily at the respiratory epithelium, and mice lacking CXCL16 also had decreased CD8 TRM cells in the airways. Finally, blocking CXCL16 inhibited the steady-state maintenance of airway TRM cells. Thus, the CXCR6/CXCL16 signaling axis controls the localization of TRM cells to different compartments of the lung and maintains airway TRM cells.

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<![CDATA[A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2–mediated inflammation]]> https://www.researchpad.co/article/elastic_article_15292 Group 2 innate lymphoid cells (ILC2s) possess indispensable roles during type 2–mediated inflammatory diseases. Although their physiological and detrimental immune functions seem to depend on the anatomical compartment they reside, their tissue tropism and the molecular and immunological processes regulating the self-renewal of the local pool of ILC2s in the context of inflammation or infection are incompletely understood. Here, we analyzed the role of the CC-chemokine receptor CCR8 for the biological functions of ILC2s. In vitro and in vivo experiments indicated that CCR8 is in comparison to the related molecule CCR4 less important for migration of these cells. However, we found that activated mouse and human ILC2s produce the CCR8 ligand CCL1 and are a major source of CCL1 in vivo. CCL1 signaling to ILC2s regulates their proliferation and supports their capacity to protect against helminthic infections. In summary, we identify a novel chemokine receptor–dependent mechanism by which ILC2s are regulated during type 2 responses.

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<![CDATA[Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2]]> https://www.researchpad.co/article/N47ae0984-aed2-400d-b024-8d4692148a59

Cytokines and lipid mediators are key regulators of inflammation; but how they are mechanistically linked is poorly understood. Here, Mukhopadhyay et al. show a novel regulation between cytokine IL-10 and lipid mediator PGE2 that functionally connects them to intestinal inflammation.

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<![CDATA[Mechanism of differential Zika and dengue virus neutralization by a public antibody lineage targeting the DIII lateral ridge]]> https://www.researchpad.co/article/N2ed74a52-d44b-44de-828b-97ef11affa0f

Evaluation of the human antibody response to Zika virus has identified common germline-derived mAbs capable of cross flavivirus neutralization. Zhao et al. provide a detailed mechanistic understanding of how flavivirus infections are prevented in a strain-specific manner by a representative mAb.

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<![CDATA[Biallelic mutation of HSD17B4 induces middle age–onset spinocerebellar ataxia]]> https://www.researchpad.co/article/N4b558b06-8845-4208-b423-3e434f803484

Objective

To determine the genetic underpinnings of slowly progressive spinocerebellar ataxia, autosomal recessive (SCAR), we performed exome analysis and examined the relationship between clinical severity and functional change induced by the mutation.

Methods

Homozygosity fingerprinting and exome sequencing were performed to identify causative mutations in 2 consanguineous families. We assessed the expression of D-bifunctional protein (DBP) and the amount of dimerized DBP in fibroblasts by immunoblot and quantitative reverse transcription PCR. The pathogenicity of the mutation was evaluated using the Combined Annotation-Dependent Depletion (CADD) scores; these results were compared with the scores of previously reported mutations.

Results

We identified a homozygous mutation as causative of middle age–onset SCAR: p.Ala175Thr, which is located in HSD17B4 that encodes peroxisomal DBP. The patients developed cerebellar ataxia, and the subsequent progression was slow. The symptoms presented were milder than those in previously reported cases. The messenger RNA expression levels were normal, but protein levels were diminished. Dimerization of DBP was also reduced. The CADD score of the identified mutation was lower than those of previously reported mutations.

Conclusions

This is the report of middle age–onset DBP deficiency. Residual functional DBP caused relatively mild symptoms in the affected patients, i.e., slowly progressive ataxia and hearing loss. This study broadens the scope of DBP deficiency phenotypes and indicates that CADD scores may be used to estimate the severity of DBP deficiencies.

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<![CDATA[Inherited IL-18BP deficiency in human fulminant viral hepatitis]]> https://www.researchpad.co/article/Ne7f3a1f6-1e5b-4764-8b97-962cbded256d

We report autosomal recessive IL-18BP deficiency in a child who died of fulminant hepatitis upon infection with hepatitis A virus. Deficiency of IL-18BP leads to excessive IL-18 activity and uncontrolled IL-18–mediated hepatotoxicity in the infected liver.

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<![CDATA[IL-27 promotes the expansion of self-renewing CD8+ T cells in persistent viral infection]]> https://www.researchpad.co/article/N333ba714-7c54-4a16-a733-368829e4a021

CXCR5+ TCF1+ CD8+ T cells sustain responses during persistent viral infection and mediate the proliferative burst following anti-PD1 treatment. Huang et al. show that IL-27 supports rapid division of these cells by competing with type 1 interferon for STAT1, driving IRF1 expression and preventing cell death.

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<![CDATA[The complex of MCMV proteins and MHC class I evades NK cell control and drives the evolution of virus-specific activating Ly49 receptors]]> https://www.researchpad.co/article/N989f348c-e147-4453-b328-a46bf1b383d8

Železnjak et al. demonstrate that two MCMV-encoded proteins interact with MHC I molecules, forming an altered-self complex that prevents missing self recognition by increasing specificity for inhibitory Ly49 receptors. This led to the evolution of CMV-specific activating Ly49s.

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<![CDATA[CXCR4 regulates Plasmodium development in mouse and human hepatocytes]]> https://www.researchpad.co/article/Ncc76c91f-2728-4c8b-91aa-a4526850f910

In the livers of Plasmodium-infected mammalian hosts, the rod-shaped mosquito-stage parasites develop into spherical exoerythrocytic forms, subsequently forming the erythrocyte-stage parasites and eventually causing malaria. Here, Bando et al. identify CXCR4 as a host factor for Plasmodium liver-stage development.

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<![CDATA[Mg2+ regulation of kinase signaling and immune function]]> https://www.researchpad.co/article/Nb4376ba2-f8ca-45c1-ad83-13cee032876b

A Mg2+-dependent mechanism regulates proximal T cell receptor signaling by modulating ITK activity through a low-affinity Mg2+ binding pocket in the catalytic domain. Dietary Mg2+ deprivation in mice impairs T cell activation and T cell–mediated immunity against influenza.

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<![CDATA[Relationship between latent and rebound viruses in a clinical trial of anti–HIV-1 antibody 3BNC117]]> https://www.researchpad.co/article/5c910795d5eed0c4841a458f

In the setting of a clinical trial evaluating the anti–HIV-1 antibody 3BNC117, Cohen et al. demonstrate that rebound viruses that emerge following interruption of antiretroviral therapy are distinct from circulating latent viruses. Rebound viruses often appear to be recombinants between isolated latent viruses.

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<![CDATA[The human CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses]]> https://www.researchpad.co/article/5c910786d5eed0c4841a4439

de Jong et al. show that loss-of-function mutations in CIB1 are responsible for epidermodysplasia verruciformis, a cutaneous disease caused by human β-papillomavirus (β-HPV) infections, and that CIB1 forms a complex with EVER proteins, acting as a restriction factor against HPV.

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<![CDATA[Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation]]> https://www.researchpad.co/article/5c91078dd5eed0c4841a44d1

Lee et al. generate knock-in mice with critical residues mutated in caspase-11 and GSDMD. This is the first compelling genetic evidence to demonstrate the critical roles of caspase-11 catalytic and auto-proteolytic activities, as well as GSDMD cleavage in a physiological response to LPS.

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<![CDATA[B cell adaptor for PI3-kinase (BCAP) modulates CD8+ effector and memory T cell differentiation]]> https://www.researchpad.co/article/5c91079ad5eed0c4841a4619

Singh et al. show that expression of B cell adaptor for PI3-kinase (BCAP) is induced upon T cell activation and that this helps control effector and memory CD8+ T cell differentiation.

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<![CDATA[Eosinophils suppress Th1 responses and restrict bacterially induced gastrointestinal inflammation]]> https://www.researchpad.co/article/5c69ecafd5eed0c48414e17d

Arnold et al. report that eosinophils in the gastrointestinal tract are conditioned by IFN-γ to restrict Th1 responses and promote tissue homeostasis. Eosinophils control Th1 cells in acute and chronic infection and in the steady state and possess bactericidal properties.

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<![CDATA[The Rho regulator Myosin IXb enables nonlymphoid tissue seeding of protective CD8+ T cells]]> https://www.researchpad.co/article/5c368382d5eed0c4841f3ff9

Moalli et al. combine in vitro CD8+ T cell motility analysis with intravital imaging of mouse tissues to identify the actomyosin regulator Myo9b as a central player for nonlymphoid tissue infiltration during adaptive immune responses by facilitating crossing of tissue barriers.

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<![CDATA[The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory Th1 cell fate determination]]> https://www.researchpad.co/article/5c368388d5eed0c4841f40ba

The balance between inflammatory IFN-γ and antiinflammatory IL-10 plays a critical role in modulating type 1 immune responses. Yu et al. show that the transcription factor Bhlhe40 serves as a molecular switch between inflammatory and antiinflammatory Th1 cells.

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<![CDATA[Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection]]> https://www.researchpad.co/article/5c36838cd5eed0c4841f417d

This study demonstrates that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is essential during Mycobacterium tuberculosis infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection.

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<![CDATA[Drawing on disorder: How viruses use histone mimicry to their advantage]]> https://www.researchpad.co/article/5c368384d5eed0c4841f4040

Viruses mimic histone proteins to gain control over gene regulatory networks, maximize replication, and suppress host antiviral immunity.

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<![CDATA[Regulating the regulator: Bhlhe40 directly keeps IL-10 in check]]> https://www.researchpad.co/article/5c36838fd5eed0c4841f4203

Huynh et al. and Yu et al. demonstrate that the transcription factor Bhlhe40 acts is a repressor of IL-10 production during infection with Mycobacterium tuberculosis or Toxoplasma gondii. Deletion of Bhlhe40 in both cases resulted in chronic infection and increased pathogen load as a consequence of increased IL-10 production.

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