We examined the role of innate cells in acquired resistance to the natural murine parasitic nematode, Nippostrongylus brasiliensis. Macrophages obtained as late as 45 days after N. brasiliensis inoculation were able to transfer accelerated parasite clearance to naive recipients. Primed macrophages adhered to larvae in vitro and triggered increased mortality of parasites. Neutrophil depletion in primed mice abrogated the protective effects of transferred macrophages and inhibited their in vitro binding to larvae. Neutrophils in parasite-infected mice showed a distinct transcriptional profile and promoted alternatively activated M2 macrophage polarization through secretory factors including IL-13. Differentially activated neutrophils in the context of a type 2 immune response therefore prime a long-lived effector macrophage phenotype that directly mediates rapid nematode damage and clearance.
Although CD31 expression on human thymocytes has been reported, a detailed analysis of CD31 expression at various stages of T cell development in the human thymus is missing. Herein, we provide a global picture of the evolution of CD31 expression from the CD34+ hematopoietic precursor to the CD45RA+ mature CD4+ and CD8+ single positive T cells. Using 9-color flow cytometry, we show that CD31 is highly expressed on CD34+ progenitors and stays high until the early double positive stage (CD3− CD4+ CD8α+β −). After β-selection, CD31 expression levels become low to undetectable. CD31 expression then increases and peaks on CD3high CD4+CD8+ double positive thymocytes. However, following positive selection, CD31 expression differs dramatically between CD4+ and CD8+ lineages: homogeneously high on CD8 SP but lower or negative on CD4 SP cells, including a subset of CD45RA+ CD31− mature CD4+ thymocytes. CD31 expression on TCRγδ thymocytes is very similar to that of CD4 SP cells. Remarkably, there is a substantial subset of semi-mature (CD45RA−) CD4 SP thymocytes that lack CD31 expression. Moreover, FOXP3+ and ICOS+ cells are over-represented in this CD31− subpopulation. Despite this CD31− CD45RA− subpopulation, the majority of egress-capable mature CD45RA+ CD4 SP thymocytes expresses CD31. The variations in CD31 expression appear to coincide with three major selection processes occurring during thymopoiesis: β-selection, positive selecion and negative selection. Considering the ability of CD31 to modulate the TCR’s activation threshold via the recruitment of tyrosine phosphatases, our results suggest a significant role for CD31 during T cell development.
Mature human thymocytes rely on S1P-R1 to migrate toward S1P. Taken in the context of murine work demonstrating that S1P is required for thymocyte egress to the periphery, our data highlight a new key chemokine for human thymocyte egress.
Summary
Staphylococcus aureus
is the most common cause of skin and soft tissue infections, yet the bacterial genetic changes associated with adaptation to human skin are not well characterized.
S. aureus
strains isolated from patients with chronic skin colonization and intermittent infection were used to determine the staphylococcal genotypes or phenotypes associated with adaptation to human skin. We demonstrate that polymorphisms in metabolic genes, particularly those involved in the tricarboxylic acid cycle, the fumarate-succinate axis, and the generation of terminal electron transporters, are unexpectedly common. These skin-adapted strains activated glycolysis and hypoxia-inducible factor-1α, interleukin (IL)-1β, and IL-18 release from keratinocytes and promoted dermatopathology equivalent to a methicillin-resistant
Staphylococcus aureus
USA300 control in a murine model of infection. However, in contrast to USA300, a skin-adapted isolate failed to generate protection from a secondary infectious challenge. Within the context of human skin, there appears to be selection for
S. aureus
metabolic adaptive changes that promote glycolysis and maintain pathogenicity.
In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity'). In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity. Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months. Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype. Additionally, persistently infected mice displayed a dramatic increase in circulating nonclassical monocytes, a phenomenon that we also observed in humans with both chronic Plasmodium exposure and asymptomatic infection. Following pharmacological clearance of infection, previously persistently infected mice could not control a secondary challenge, indicating that persistent infection disrupts the sterilizing immunity that typically develops in mouse models of acute infection. This study establishes an animal model of asymptomatic, persistent Plasmodium infection that recapitulates several central aspects of the immune response in chronically exposed humans. As such, it provides a novel tool for dissection of immune responses that may prevent development of sterilizing immunity and limit pathology during infection.
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