IL-4 induces CD22 expression to restrain the effector program of self-reactive virtual memory T cells

Parasitic helminths induce the production of interleukin (IL)-4 which causes the expansion of virtual memory CD8+ T cells (TVM), a cell subset contributing to the control of viral coinfection. However, the mechanisms regulating IL-4-dependent TVM activation and expansion during worm infection remain ill defined. We used single-cell RNA sequencing of CD8+ T cells to investigate IL-4-dependent TVM responses upon helminth infection in mice. Gene signature analysis of CD8+ T cells identified a cell cluster marked by CD22, a canonical regulator of B cell activation, as a specific and selective surface marker of IL-4-induced TVM cells. CD22+ TVM were enriched for IFN-γ and granzyme A and retained a diverse TCR repertoire, while enriched in CDR3 sequences with features of self-reactivity. Deletion of CD22 expression in CD8+ T cells enhanced TVM responses to helminth infection, indicating that this inhibitory receptor modulates TVM responses. Thus, helminth-induced IL-4 drives the expansion and activation of self-reactive TVM in the periphery that is counter-inhibited by CD22

Elp3-mediated codon-dependent translation promotes mTORC2 activation and regulates macrophage polarization.

peer reviewedMacrophage polarization is a process whereby macrophages acquire distinct effector states (M1 or M2) to carry out multiple and sometimes opposite functions. We show here that translational reprogramming occurs during macrophage polarization and that this relies on the Elongator complex subunit Elp3, an enzyme that modifies the wobble uridine base U34 in cytosolic tRNAs. Elp3 expression is downregulated by classical M1-activating signals in myeloid cells, where it limits the production of pro-inflammatory cytokines via FoxO1 phosphorylation, and attenuates experimental colitis in mice. In contrast, alternative M2-activating signals upregulate Elp3 expression through a PI3K- and STAT6-dependent signaling pathway. The metabolic reprogramming linked to M2 macrophage polarization relies on Elp3 and the translation of multiple candidates, including the mitochondrial ribosome large subunit proteins Mrpl3, Mrpl13, and Mrpl47. By promoting translation of its activator Ric8b in a codon-dependent manner, Elp3 also regulates mTORC2 activation. Elp3 expression in myeloid cells further promotes Wnt-driven tumor initiation in the intestine by maintaining a pool of tumor-associated macrophages exhibiting M2 features. Collectively, our data establish a functional link between tRNA modifications, mTORC2 activation, and macrophage polarization

IL-4 induces CD22 expression to restrain the effector program of self-reactive virtual memory T cells

Abstract Parasitic helminths induce the production of interleukin (IL)-4 which causes the expansion of virtual memory CD8+ T cells (Tvm), a cell subset contributing to the control of viral coinfection. However, the mechanisms regulating IL-4-dependent Tvm activation and expansion during worm infection remain ill defined. We used single-cell RNA sequencing of CD8+ T cells to investigate IL-4-dependent Tvm responses upon helminth infection in mice. Gene signature analysis of CD8+ T cells identified a cell cluster marked by CD22, a canonical regulator of B cell activation, as a specific and selective surface marker of IL-4-induced Tvm cells. CD22+ Tvm were enriched for IFN-γ and granzyme A and retained a diverse TCR repertoire, while enriched in CDR3 sequences with features of self-reactivity. Deletion of CD22 expression in CD8+ T cells enhanced Tvm responses to helminth infection, indicating that this inhibitory receptor modulates Tvm responses. Thus, helminth-induced IL-4 drives the expansion and activation of self-reactive Tvm in the periphery that is counter-inhibited by CD22

Mobile Plant Disease Classifier, Trained with a Small Number of Images by the End User

Mobile applications that can be used for the training and classification of plant diseases are described in this paper. Professional agronomists can select the species and their diseases that are supported by the developed tool and follow an automatic training procedure using a small number of indicative photographs. The employed classification method is based on features that represent distinct aspects of the sick plant such as, for example, the color level distribution in the regions of interest. These features are extracted from photographs that display a plant part such as a leaf or a fruit. Multiple reference ranges are determined for each feature during training. When a new photograph is analyzed, its feature values are compared with the reference ranges, and different grades are assigned depending on whether a feature value falls within a range or not. The new photograph is classified as the disease with the highest grade. Ten tomato diseases are used as a case study, and the applications are trained with 40–100 segmented and normalized photographs for each disease. An accuracy between 93.4% and 96.1% is experimentally measured in this case. An additional dataset of pear disease photographs that are not segmented or normalized is also tested with an average accuracy of 95%

Parasitic worms affect virus coinfection: a mechanistic overview.

peer reviewedHelminths are parasitic worms that coevolve with their host, usually resulting in long-term persistence through modulating host immunity. The multifarious mechanisms altering the immune system induced by helminths have significant implications on the control of coinfecting pathogens such as viruses. Here, we explore the recent literature to highlight the main immune alterations and mechanisms that affect the control of viral coinfection. Insights from these mechanisms are valuable in the understanding of clinical observations in helminth-prevalent areas and in the design of new therapeutic and vaccination strategies to control viral diseases

IL-4rα-dependent Lung Macrophage Responses To Helminths Increase Permissiveness To Gammaherpesvirus Infection

Helminth infection conditions lung macrophages in the long term, but little is known about how helminths affect the lung macrophage responses to respiratory viral coinfection. While comparing BALB/c and C57BL/6 mice, we found that helminth infection in C57BL/6 mice resulted in enhanced permissiveness to a subsequent infection with murid gammaherpesvirus 4 (MuHV-4), and that viral early tropism was mainly restricted to lung macrophages. Helminth infection resulted in enhanced type 2 airway inflammation and M(IL-4) polarization of interstitial macrophages (IntMs) in C57BL/6 mice, associated with an IL-4Rα-dependent disappearance reaction of alveolar macrophages (AlvMs) and enriched monocyte-derived IntMs proportions. Competent IL-4Rα responsiveness or intra-tracheal instillation of recombinant IL-4 or IL-13 significantly resulted in reduced numbers of AlvMs and enriched IntMs as well as increased permissiveness to MuHV-4 infection, which was restricted to AlvMs. Thus, direct IL-4Rα signaling during helminth infection affects macrophage permissiveness to gammaherpesvirus infection

IL-4 RECEPTOR SIGNALING REGULATES LUNG MACROPHAGES DURING HELMINTH COINFECTION RESULTING IN ENHANCED GAMMAHERPESVIRUS PERMISSIVENESS

peer reviewe

Il-4rα-dependent Lung Macrophage Response To Helminth Increases Permissiveness To Gammaherpesvirus Infection

Helminth infection conditions lung macrophages in the long term, but little is known about how helminths affect the lung macrophage responses to respiratory viral coinfection. While comparing BALB/c and C57BL/6 mice, we found that helminth infection in C57BL/6 mice resulted in enhanced permissiveness to a subsequent infection with murid gammaherpesvirus 4 (MuHV-4), and that viral early tropism was mainly restricted to lung macrophages. Helminth infection resulted in enhanced type 2 airway inflammation and M(IL-4) polarization of interstitial macrophages (IntMs) in C57BL/6 mice, associated with an IL-4Rα-dependent disappearance reaction of alveolar macrophages (AlvMs) and enriched monocyte-derived IntMs proportions. Competent IL-4Rα responsiveness or intra-tracheal instillation of recombinant IL-4 or IL-13 significantly resulted in reduced numbers of AlvMs and enriched IntMs as well as increased permissiveness to MuHV-4 infection, which was restricted to AlvMs. Thus, direct IL-4Rα signaling during helminth infection affects macrophage permissiveness to gammaherpesvirus infection

IL-4 receptor signaling regulates lung macrophages during helminth coinfection resulting in enhanced gammaherpesvirus permissiveness

Helminth infection conditions lung macrophages in the long term, but little is known about how helminths affect the lung macrophage responses to respiratory viral coinfection. While comparing BALB/c and C57BL/6 mice, we found that helminth infection in C57BL/6 mice resulted in enhanced permissiveness to a subsequent infection with murid gammaherpesvirus 4 (MuHV-4), and that viral early tropism was mainly restricted to lung macrophages. Helminth infection resulted in enhanced type 2 airway inflammation and M(IL-4) polarization of interstitial macrophages (IntMs) in C57BL/6 mice, associated with an IL-4Rα-dependent disappearance reaction of alveolar macrophages (AlvMs) and enriched monocyte-derived IntMs proportions. Competent IL-4Rα responsiveness or intra-tracheal instillation of recombinant IL-4 or IL-13 significantly resulted in reduced numbers of AlvMs and enriched IntMs as well as increased permissiveness to MuHV-4 infection, which was restricted to AlvMs. Thus, direct IL-4Rα signaling during helminth infection affects macrophage permissiveness to gammaherpesvirus infection

Single-cell proteomics and transcriptomics capture eosinophil development and identify the role of IL-5 in their lineage transit amplification

The activities, ontogeny, and mechanisms of lineage expansion of eosinophils are less well resolved than those of other immune cells, despite the use of biological therapies targeting the eosinophilia-promoting cytokine interleukin (IL)-5 or its receptor, IL-5Rα. We combined single-cell proteomics and transcriptomics and generated transgenic IL-5Rα reporter mice to revisit eosinophilopoiesis. We reconciled human and murine eosinophilopoiesis and provided extensive cell-surface immunophenotyping and transcriptomes at different stages along the continuum of eosinophil maturation. We used these resources to show that IL-5 promoted eosinophil-lineage expansion via transit amplification, while its deletion or neutralization did not compromise eosinophil maturation. Informed from our resources, we also showed that interferon response factor-8, considered an essential promoter of myelopoiesis, was not intrinsically required for eosinophilopoiesis. This work hence provides resources, methods, and insights for understanding eosinophil ontogeny, the effects of current precision therapeutics, and the regulation of eosinophil development and numbers in health and disease.</p