Murine but Not Human Basophil Undergoes Cell-Specific Proteolysis of a Major Endoplasmic Reticulum Chaperone

Basophil has been implicated in anti-parasite defense, allergy and in polarizing T(H)2 response. Mouse model has been commonly used to study basophil function although the difference between human and mouse basophils is underappreciated. As an essential chaperone for multiple Toll-like receptors and integrins in the endoplasmic reticulum, gp96 also participates in general protein homeostasis and in the ER unfolded protein response to ensure cell survival during stress. The roles of gp96 in basophil development are unknown.We genetically delete gp96 in mice and examined the expression of gp96 in basophils by Western blot and flow cytometry. We compared the expression pattern of gp96 between human and mouse basophils.We found that gp96 was dispensable for murine basophil development. Moreover, gp96 was cleaved by serine protease(s) in murine but not human basophils leading to accumulation of a nun-functional N-terminal ∼50 kDa fragment and striking induction of the unfolded protein response. The alteration of gp96 was unique to basophils and was not observed in any other cell types including mast cells. We also demonstrated that the ectopic expression of a mouse-specific tryptase mMCP11 does not lead to gp96 cleavage in human basophils.Our study revealed a remarkable biochemical event of gp96 silencing in murine but not human basophils, highlighting the need for caution in using mouse models to infer the function of basophils in human immune response. Our study also reveals a novel mechanism of shutting down gp96 post-translationally in regulating its function

Chronic Infection Drives Expression of the Inhibitory Receptor CD200R, and Its Ligand CD200, by Mouse and Human CD4 T Cells

Certain parasites have evolved to evade the immune response and establish chronic infections that may persist for many years. T cell responses in these conditions become muted despite ongoing infection. Upregulation of surface receptors with inhibitory properties provides an immune cell-intrinsic mechanism that, under conditions of chronic infection, regulates immune responses and limits cellular activation and associated pathology. The negative regulator, CD200 receptor, and its ligand, CD200, have been shown to regulate macrophage activation and reduce pathology following infection. We show that CD4 T cells also increase expression of inhibitory CD200 receptors (CD200R) in response to chronic infection. CD200R was upregulated on murine effector T cells in response to infection with bacterial, Salmonella enterica, or helminth, Schistosoma mansoni, pathogens that respectively drive predominant Th1- or Th2-responses. In vitro chronic and prolonged stimuli were required for the sustained upregulation of CD200R, and its expression coincided with loss of multifunctional potential in T effector cells during infection. Importantly, we show an association between IL-4 production and CD200R expression on T effector cells from humans infected with Schistosoma haematobium that correlated effectively with egg burden and, thus infection intensity. Our results indicate a role of CD200R:CD200 in T cell responses to helminths which has diagnostic and prognostic relevance as a marker of infection for chronic schistosomiasis in mouse and man

Group 2 Innate Lymphoid Cell Proportions Are Diminished in Young Helminth Infected Children and Restored by Curative Anti-helminthic Treatment

BACKGROUND:Group 2 Innate lymphoid cells (ILC2s) are innate cells that produce the TH2 cytokines IL-5 and IL-13. The importance of these cells has recently been demonstrated in experimental models of parasitic diseases but there is a paucity of data on ILC2s in the context of human parasitic infections and in particular of the blood dwelling parasite Schistosoma haematobium. METHODOLOGY/PRINCIPAL FINDINGS:In this case-control study human peripheral blood ILC2s were analysed in relation to infection with the helminth parasite Schistosoma haematobium. Peripheral blood mononuclear cells of 36 S. haematobium infected and 36 age and sex matched uninfected children were analysed for frequencies of ILC2s identified as Lin-CD45+CD127+CD294+CD161+. ILC2s were significantly lower particularly in infected children aged 6-9 years compared to healthy participants. Curative anti-helminthic treatment resulted in an increase in levels of the activating factor TSLP and restoration of ILC2 levels. CONCLUSION:This study demonstrates that ILC2s are diminished in young helminth infected children and restored by removal of the parasites by treatment, indicating a previously undescribed association between a human parasitic infection and ILC2s and suggesting a role of ILC2s before the establishment of protective acquired immunity in human schistosomiasis

A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells

Dendritic cells (DCs) direct CD4+ T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4+ T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation