A pinboard by
Sebastian Scheer

PostDoc, Monash University


Innate lymphoid cells (ILCs) are a recently identified population of hematopoietic cells that bridge innate and adaptive immunity. In the lung, a subset of ILCs, ILC2s which express the transcription factor GATA3, rapidly respond to IL-25, thymic stromal lymphopoietin (TSLP) and IL-33, cytokines produced by damaged or stressed airway epithelial cells. This cytokine-induced activation of ILC2s results in the production of IL-5 and IL-13, cytokines important for the expansion of eosinophils and alternative (M2) macrophage activation. As IL-5, IL-13, eosinophilia and M2 polarization are all hallmarks of allergic lung inflammation, ILC2s represent an important therapeutic target for treating pulmonary inflammatory diseases. Recently, our group reported that ILC2 development and function is severely impaired in the absence of the methyltransferase G9a and others have reported that NF-B transcription factors were added to the list of G9a binding proteins, with G9a found to interact with the NF-kB family members NF-kB1, RelA, c-Rel and RelB in a proteomic screen. We therefore hypothesized that the canonical NF-kB family member c-Rel has a critical, non-redundant roles in ILC2 development, differentiation and function. Our results show that ex vivo generated ILC2s respond to IL-33 via c-Rel, as determined by EMSA. Analysis of c-Rel KO mice show normal frequencies of ILC2s in the bone marrow and lungs, demonstrating that c-Rel is dispensable for ILC2 development and homeostasis. However, when intranasally challenged with IL-33, c-Rel KO mice show decreased expansion of ILC2s in the lung and less expression of IL-5 and IL-13. In two different models of airway inflammation (papain and house dust mite allergy) c-Rel KO mice show less eosinophilia compared to WT mice, thus demonstrating the importance of c-Rel in lung inflammation. Taken together, we show that c-Rel has important functions maintaining the inflammatory character of ILC2s.


S. mansoni bolsters anti-viral immunity in the murine respiratory tract.

Abstract: The human intestinal parasite Schistosoma mansoni causes a chronic disease, schistosomiasis or bilharzia. According to the current literature, the parasite induces vigorous immune responses that are controlled by Th2 helper cells at the expense of Th1 helper cells. The latter cell type is, however, indispensable for anti-viral immune responses. Remarkably, there is no reliable literature among 230 million patients worldwide describing defective anti-viral immune responses in the upper respiratory tract, for instance against influenza A virus or against respiratory syncitial virus (RSV). We therefore re-examined the immune response to a human isolate of S. mansoni and challenged mice in the chronic phase of schistosomiasis with influenza A virus, or with pneumonia virus of mice (PVM), a mouse virus to model RSV infections. We found that mice with chronic schistosomiasis had significant, systemic immune responses induced by Th1, Th2, and Th17 helper cells. High serum levels of TNF-α, IFN-γ, IL-5, IL-13, IL-2, IL-17, and GM-CSF were found after mating and oviposition. The lungs of diseased mice showed low-grade inflammation, with goblet cell hyperplasia and excessive mucus secretion, which was alleviated by treatment with an anti-TNF-α agent (Etanercept). Mice with chronic schistosomiasis were to a relative, but significant extent protected from a secondary viral respiratory challenge. The protection correlated with the onset of oviposition and TNF-α-mediated goblet cell hyperplasia and mucus secretion, suggesting that these mechanisms are involved in enhanced immune protection to respiratory viruses during chronic murine schistosomiasis. Indeed, also in a model of allergic airway inflammation mice were protected from a viral respiratory challenge with PVM.

Pub.: 15 Nov '14, Pinned: 24 Aug '17

Early-life antibiotic treatment enhances the pathogenicity of CD4+ T cells during intestinal inflammation.

Abstract: The incidence of inflammatory bowel diseases (IBDs) has steadily increased in recent decades-a phenomenon that cannot be explained by genetic mutations alone. Other factors, including the composition of the intestinal microbiome, are potentially important contributors to the increased occurrence of this group of diseases. Previous reports have shown a correlation between early-life antibiotic (Abx) treatment and an increased incidence of IBD. In this report, we investigated the effects of early-life Abx treatments on the pathogenicity of CD4(+) T cells using an experimental T cell transfer model of IBD. Our results show that CD4(+) T cells isolated from adult mice that had been treated with Abx during gestation and in early life induced a faster onset of IBD in Rag1-deficient mice compared with CD4(+) T cells of untreated mice. Ex vivo functional analyses of IBD-inducing CD4(+) T cells did not show significant differences in their immunologic potential ex vivo, despite their in vivo phenotype. However, genome-wide gene-expression analysis revealed that these cells displayed dysregulated expression of genes associated with cell-cycle regulation, metabolism, and cellular stress. Analysis of Abx-treated CD4(+) T cell donors showed systemically elevated levels of the stress hormone corticosterone throughout life compared with untreated donors. The cohousing of Abx-treated mice with untreated mice decreased serum corticosterone, and a consequent transfer of the cells from cohoused mice into Rag1-deficient mice restored the onset and severity of disease to that of untreated animals. Thus, our results suggest that early-life Abx treatment results in a stress response with high levels of corticosterone that influences CD4(+) T cell function.

Pub.: 31 Dec '16, Pinned: 24 Aug '17