IL-6 prevents Th2 cell polarization by promoting SOCS3-dependent suppression of IL-2 signaling

Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE levels. However, the underlying mechanism by which IL-6 prevents the development of Th2-driven diseases remains unknown. Using a model of house dust mite (HDM)-induced Th2 cell differentiation and allergic airway inflammation, we showed that IL-6 signaling in allergen-specific T cells was required to prevent Th2 cell differentiation and the subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. We found that IL-6 turned off IL-2 signaling during early T-cell activation and thus inhibited Th2 priming. Mechanistically, IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of Suppressor Of Cytokine Signaling 3 (SOCS3). This mechanism could be mimicked by pharmacological Janus Kinase-1 (JAK1) inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions.

Diabetes-related impairment in bone strength is established early in the life course

AIM: To evaluate properties of bone quantity/quality using young non-obese Type 1(T1D)-diabetic(NOD) prone and syngenic non-diabetic(NOD.scid) mice.METHODS: Quantitative bone assessment of tibia was conducted using dual-energy X-ray absorptiometry(DXA) for the evaluation of body mass,bone mineral content,body fat mass and lean mass.Qualitative assessment was accomplished by three-point breakage for assessment of force to failure and micro-computed tomography for evaluation of trabecular and cortical properties of bone.In addition,fasting blood was evaluated prior to sacrifice at week eleven and fifteen to evaluate and compare glucose homeostasis between the strains of mice.RESULTS: Our findings support a perturbation in the relationship between bone quantity,quality,and subsequently,the association between structure and strength.There were no differences in DXA-assessed body composition(body fat,% fat mass and lean mass) and bone composition(bone mineral content and bone mineral density) between strains.However,relative to NOD.scid,NOD mice had lower trabecular bone volume,relative trabecular bone volume,trabecular number and trabecular total material density(P < 0.05).Conversely,NOD mice had greater cortical total mean volume(P < 0.05).General linear models analysis adjusted for body weight revealed a significant contribution of T1D to bone health as early as 5 wk.CONCLUSION: It is well-established that diabetes is a significant risk factor for increased fractures,although the underlying mechanisms are not fully understood.Investigation of bone parameters encompassing strength and structure early in the life course will facilitate the elucidation of the pathogenesis of impaired bone integrity.

Protein-based profiling of the human IgA1 clonal repertoire revealed shared clones of serum polymeric IgA1 and milk secretory IgA1

Human adaptive immunity involves the production and secretion of antibodies by differentiated B cells(ie.,antibody-secreting cells,also called plasma cells)in response to antigens.These secreted antigen-specific antibodies are immunoglobulins that are present at substantial concentrations in blood,mucosal secretions,and breast milk.Structurally,human immunoglobulins consist of two identical heavy(H)chains and two identical light(L)chains that are connected by disulfide bridges to form a homodimer of heterodimers(ie.,H+Ll2).Each heterodimer consists of one H chain linked with one L chain,whereas the homodimer is formed by linking two H chains together.The genes for both the L and H chains are encoded by ligated gene segments that are genetically rearranged during V(D)J recombination,a process that endows each B cell with a unique receptor,giving rise to the enormous diversity of the B-cell antigen receptor repertoire.

Immunobiology of congenital cytomegalovirus infection of the central nervous system--the murine cytomegalovirus model

Congenital human cytomegalovirus infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and hearing defects. Strict species specificity of cytomegaloviruses has restricted the scope of studies of cytomegalovirus infection in animal models. To investigate the pathogenesis of congenital human cytomegalovirus infection, we developed a mouse cytomegalovirus model that recapitulates the major characteristics of central nervous system infection in human infants, including the route of neuroinvasion and neuropathological findings. Following intraperitoneal inoculation of newborn animals with mouse cytomegalovirus, the virus disseminates to the central nervous system during high-level viremia and replicates in the brain parenchyma, resulting in a focal but widespread, non-necrotizing encephalitis. Central nervous system infection is coupled with the recruitment of resident and peripheral immune cells as well as the expression of a large number of pro-inflammatory cytokines. Although infiltration of cellular constituents of the innate immune response characterizes the early immune response in the central nervous system, resolution of productive infection requires virus-specific CD8＋ T cells. Perinatal mouse cytomegalovirus infection results in profoundly altered postnatal development of the mouse central nervous system and long-term motor and sensory disabilities. Based on an enhanced understanding of the pathogenesis of this infection, prospects for novel intervention strategies aimed to improve the outcome of congenital human cytomegalovirus infection are proposed.

Inscribing the core memories of killers

Recent studies on natural killer(NK)cells have challenged the dogma that immunological memory is a phenomenon restricted to the adaptive immune system.Specific interactions between the NK cell receptor Ly49H and the murine cytomegalovirus virus(MCMV)-encoded glycoprotein m157 result in selective expansion of the Ly49H+NK cell subpopulation and the establishment of a long-lived memory-like population.1–3 Further,memory NK cells show augmented IFNγresponses,and transfer of the memory population into naive mice confers enhanced protection against infection-induced mortality.1 These observations along with cytotoxicity and cytokine secretion functions that overlap with CD8 T cells have led to the description of NK cells as a bridge between the innate and adaptive immune systems.

Polymer-virus core-shell structures prepared via co-assembly and template synthesis methods

Bionanoparticles(BNPs),consisting of virus and virus-like assemblies,have attracted much attention in the biomedical field for their applications such as imaging and targeted drug delivery,owing to their well-defined structures and well-controlled chemistries.BNPs-based core-shell structures provide a unique system for the investigation of biological interactions such as protein-protein and protein-carbohydrate interactions.However,it is still a challenge to prepare the BNPs-based core-shell structures.Herein,we describe(i) co-assembly method and(ii) template synthesis method in the development of polymer-BNPs core-shell structures.These two methods can be divided into three different systems.In system A,different polymers including poly(2-vinylpyridine)(P2VP),poly(4-vinylpyridine)(P4VP) and poly(ε-caprolactone)-block-poly(2-vinylpyridine)(PCL-b-P2VP) can form a raspberry-like structure with BNPs.In system B,polystyrene(PS) spheres end capped with free amine and BNPs can form a core-shell structure.In System C,layer-by-layer(LBL) method is used to prepare positive charged PS particles,which can be used as a template to form the core-shell structures with BNPs.These two methods may open a new way for preparing novel protein-based functional materials for potential applications in the biomedical field.

Oncogenic viruses and cancer

This special issue of the journal is dedicated to the important topic of oncogenic viruses and cancer.It contains seven review articles covering all known oncogenic viruses except for human T-lymphotropic virus type1(HTLV-1).These review articles are contributed by experts on specific viruses and their associated human cancers.Viruses account for about 20%of total human cancer cases.Although many viruses can cause various tumors in animals,only seven of them

Polyomavirus interaction with the DNA damage response

Viruses are obligate intracellular parasites that subvert cellular metabolism and pathways to mediate their own replication—normally at the expense of the host cell. Polyomaviruses are a group of small DNA viruses, which have long been studied as a model for eukaryotic DNA replication. Polyomaviruses manipulate host replication proteins, as well as proteins involved in DNA maintenance and repair, to serve as essential cofactors for productive infection. Moreover, evidence suggests that polyomavirus infection poses a unique genotoxic threat to the host cell. In response to any source of DNA damage, cells must initiate an effective DNA damage response(DDR) to maintain genomic integrity, wherein two protein kinases, ataxia telangiectasia mutated(ATM) and ATM- and Rad3-related(ATR), are major regulators of DNA damage recognition and repair. Recent investigation suggests that these essential DDR proteins are required for productive polyomavirus infection. This review will focus on polyomaviruses and their interaction with ATMand ATR-mediated DNA damage responses and the effect of this interaction on host genomic stability.

Tissue-resident T cells lose their SIP_1 exit visas

CD8 T cells play critical roles in controlling intracellular pathogensand tumors. To accomplish this the small number of antigen-inexperienced naive CD8 T cells that are capable of recognizing the antigen of interest must first become primed. These initial activaion events occur while the responding T cells are sequestered within lymph nodes, but many of the cells subsequently egress into the periphery and migrate into other organs where they can fulfill their principle mission of identifying and eliminating infected or malignant target cells.