IL-27 Imparts Immunoregulatory Function to Human NK Cell Subsets

Interleukin-27 (IL-27) is a cytokine with multiple roles in regulating the immune response, but its effect on human CD56bright and CD56dim NK cell subsets is unknown. NK cell subsets interact with other components of the immune system, leading to cytotoxicity or immunoregulation depending on stimulating factors. We found that IL-27 treatment results in increased IL-10 and IFN-γ expression, increased viability and decreased proliferation in both CD56bright and CD56dim NK cell subsets. More importantly, IL-27 treatment imparts regulatory activity to CD56bright NK cells, which mediates its suppressive function on T cells in a contact-dependent manner. There is growing evidence that CD56bright NK cell-mediated immunoregulation plays an important role in the control of autoimmunity. Thus, understanding the role of IL-27 in NK cell function has important implications for treatment of autoimmune disorders

RNase L Mediated Protection from Virus Induced Demyelination

IFN-α/β plays a critical role in limiting viral spread, restricting viral tropism and protecting mice from neurotropic coronavirus infection. However, the IFN-α/β dependent mechanisms underlying innate anti-viral functions within the CNS are poorly understood. The role of RNase L in viral encephalomyelitis was explored based on its functions in inhibiting translation, inducing apoptosis, and propagating the IFN-α/β pathway through RNA degradation intermediates. Infection of RNase L deficient (RL−/−) mice with a sub-lethal, demyelinating mouse hepatitis virus variant revealed that the majority of mice succumbed to infection by day 12 p.i. However, RNase L deficiency did not affect overall control of infectious virus, or diminish IFN-α/β expression in the CNS. Furthermore, increased morbidity and mortality could not be attributed to altered proinflammatory signals or composition of cells infiltrating the CNS. The unique phenotype of infected RL−/− mice was rather manifested in earlier onset and increased severity of demyelination and axonal damage in brain stem and spinal cord without evidence for enhanced neuronal infection. Increased tissue damage coincided with sustained brain stem infection, foci of microglia infection in grey matter, and increased apoptotic cells. These data demonstrate a novel protective role for RNase L in viral induced CNS encephalomyelitis, which is not reflected in overall viral control or propagation of IFN-α/β mediated signals. Protective function is rather associated with cell type specific and regional restriction of viral replication in grey matter and ameliorated neurodegeneration and demyelination

Coxsackievirus infection induces direct pancreatic β cell killing but poor antiviral CD8+ T cell responses.

This is the final version. Available on open acess from the American Association for the Advancement of Science via the DOI in this record. Data and materials availability: Immunopeptidomics datasets have been deposited under PRIDE: PXD042711. All other data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. All unique/stable reagents generated in this study can be provided by R.M. pending scientific review and a completed materials transfer agreement. Requests should be submitted to roberto.mallone@ inserm.fr.Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β cell autoimmunity and type 1 diabetes. We investigated how CVB affects human β cells and anti-CVB T cell responses. β cells were efficiently infected by CVB in vitro, down-regulated human leukocyte antigen (HLA) class I, and presented few, selected HLA-bound viral peptides. Circulating CD8+ T cells from CVB-seropositive individuals recognized a fraction of these peptides; only another subfraction was targeted by effector/memory T cells that expressed exhaustion marker PD-1. T cells recognizing a CVB epitope cross-reacted with β cell antigen GAD. Infected β cells, which formed filopodia to propagate infection, were more efficiently killed by CVB than by CVB-reactive T cells. Our in vitro and ex vivo data highlight limited CD8+ T cell responses to CVB, supporting the rationale for CVB vaccination trials for type 1 diabetes prevention. CD8+ T cells recognizing structural and nonstructural CVB epitopes provide biomarkers to differentially follow response to infection and vaccination.Juvenile Diabetes Research FoundationSteve Morgan FoundationNational Institutes for Health Research (NIH)Agence Nationale de la RechercheFondation pour la Recherche MedicaleInnovative Medicines Initiative 2 Joint UndertakingHuman Atlas of Neonatal Development and Early Life Immunity programNovo NordiskFederal Ministry for Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.)Strategic Research Program in Diabetes at Karolinska InstitutetSwedish Child Diabetes FoundationSwedish Research Counci

Genetic and Environmental Interaction in Type 1 Diabetes: a Relationship Between Genetic Risk Alleles and Molecular Traits of Enterovirus Infection?

PURPOSE OF REVIEW: We provide an overview of the current knowledge regarding the natural history of human type 1 diabetes (T1D) and the documented associations between virus infections (in particular the enteroviruses) and disease development. We review studies that examine whether T1D-specific risk alleles in genes involved in the function of the immune system can alter susceptibility to virus infections or affect the magnitude of the host antiviral response. We also highlight where the major gaps in our knowledge exist and consider possible implications that new insights gained from the discussed gene-environment interaction studies may bring. RECENT FINDINGS: A commonality between several of the studied T1D risk variants studied is their role in modulating the host immune response to viral infection. Generally, little support exists indicating that the risk variants increase susceptibility to infection and moreover, they usually appear to predispose the immune system towards a hyper-reactive state, decrease the risk of infection, and/or favor the establishment of viral persistence. In conclusion, although the current number of studies is limited, this type of research can provide important insights into the mechanisms that are central to disease pathogenesis and further describe how genetic and environmental factors jointly influence the risk of T1D development. The latter may provide genetic markers that could be used for patient stratification and for the selection of method(s) for disease prevention.status: publishe