Cell-to-cell communication is fundamental to multicellular organisms and unicellular organisms living in a microbiome. It is thought to have evolved as a stress- or quorum-sensing mechanism in unicellular organisms. A unique cell-to-cell communication mechanism that uses reactive oxygen species (ROS) as a signal (termed the “ROS wave”) was identified in flowering plants. This process is essential for systemic signaling and plant acclimation to stress and can spread from a small group of cells to the entire plant within minutes. Whether a similar signaling process is found in other organisms is however unknown. Here, we report that the ROS wave can be found in unicellular algae, amoeba, ferns, mosses, mammalian cells, and isolated hearts. We further show that this process can be triggered in unicellular and multicellular organisms by a local stress or H 2 O 2 treatment and blocked by the application of catalase or NADPH oxidase inhibitors and that in unicellular algae it communicates important stress–response signals between cells. Taken together, our findings suggest that an active process of cell-to-cell ROS signaling, like the ROS wave, evolved before unicellular and multicellular organisms diverged. This mechanism could have communicated an environmental stress signal between cells and coordinated the acclimation response of many different cells living in a community. The finding of a signaling process, like the ROS wave, in mammalian cells further contributes to our understanding of different diseases and could impact the development of drugs that target for example cancer or heart disease.

The earliest thymic progenitors (ETPs) were recently shown to give rise to both lymphoid and myeloid cells. While the majority of ETPs are derived from IL-7Rα-positive cells and give rise exclusively to T cells, the origin of the myeloid cells remains undefined. Herein, we show both in vitro and in vivo that IL-13Rα1+ ETPs yield myeloid cells with no potential for maturation into T cells while IL-13Rα1− ETPs lack myeloid potential. Moreover, transfer of lineage-negative IL-13Rα1+ bone marrow stem cells into IL-13Rα1-deficient mice reconstituted thymic IL-13Rα1+ myeloid ETPs. Myeloid cells or macrophages in the thymus are regarded as phagocytic cells whose function is to clear apoptotic debris generated during T cell development. However, the myeloid cells derived from IL-13Rα1+ ETPs were found to perform antigen presenting functions. Thus, IL-13Rα1 defines a new class of myeloid restricted ETPs yielding Ag presenting cells that could contribute to development of T cells and the control of immunity and autoimmunity.

Summary In this study we examined the role IL-13 receptor alpha 1 (IL-13Rα1) plays in macrophage differentiation and function. The findings indicate that IL-13Rα1 is expressed on the M2 but not the M1 subset of macrophages and specifically heterodimerizes with the IL-4Rα chain to form a type II receptor, which controls the differentiation and function of these cells. Indeed, bone marrow (BM) cells from IL-13Rα1+/+ and IL-13Rα1−/− mice yield equivalent numbers of macrophages when cultured under M2 polarizing conditions. However, IL-13Rα1−/− BM cells yield a much higher number of macrophages than IL-13Rα1+/+ BM cells when the differentiation is carried out under M1-polarizing conditions. Further analyses indicated that macrophages that express IL-13Rα1 also display surface markers associated with an M2 phenotype. In addition, the IL-13Rα1+ macrophages were highly efficient in phagocytizing zymosan bioparticles both in vitro and in vivo, and supported differentiation of naïve T cells to a Th2 phenotype. Finally, when stimulated by IL-13, a cytokine that uses the heteroreceptor, the cells were able to phosphorylate STAT6 efficiently. These previously unrecognized findings indicate that IL-13Rα1 serves as a marker for M2 macrophages and the resulting heteroreceptor influences both their differentiation and function.

Type 1 diabetes involves both T helper (Th)1 and Th17 cells. While the mechanisms underlying the control of Th1 cells are relatively well defined, those operating modulation of Th17 cells remain unknown. Moreover, given that Th17 cells are plastic and can drive disease as stable or convertible T cells, effective approaches to counter type 1 diabetes would have to alter Th17 function under both circumstances. Herein, we genetically incorporated the BDC2.5-reactive p79 mimotope into an Ig molecule, and the resulting Ig-p79 was used to investigate Th17 tolerance. Accordingly, diabetogenic BDC2.5 Th17 cells were transferred into NOD mice under convertible or stable conditions and their fate was evaluated upon induction of tolerance and disease suppression by Ig-p79. The findings show that convertible (Th17 to Th1) cells display downregulation of the chemokine (C-X-C motif) receptor 3 that was associated with diminished T-box transcription factor T-bet expression, retention in the spleen, and inhibition of trafficking to the pancreas. In contrast, stable Th17 cells downregulated orphan nuclear receptor ROR-γt but increased Fas ligand expression and died by apoptosis. Thus, the final signature transcription factor shapes the mechanism of tolerance in plastic Th17 cells. These findings suggest that effective strategies against type 1 diabetes will require regimens that could drive both mechanisms of tolerance to overcome the disease.

No abstract

An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance.

Cell-to-cell communication is fundamental to multicellular organisms, as well as to unicellular organisms living in a microbiome. It is thought to have evolved as a stress- or quorum-sensing mechanism in unicellular organisms. A unique cell-to-cell communication mechanism that uses reactive oxygen species (ROS) as a signal (termed the ROS wave) was recently identified in flowering plants. This process is essential for systemic signaling and plant acclimation to stress and can spread from a small group of cells to the entire plant within minutes. Whether this signaling process is found in other organisms is however unknown. Here we report that a ROS-mediated cell-to-cell signaling process, like the ROS wave, can be found in ferns, mosses, multicellular and unicellular algae, amoeba, and mammalian cells. We further show that this process can be triggered by extracellular H2O2 application and blocked by inhibition of NADPH oxidases, and that at least in unicellular algae growing as a lawn on an agar plate, it communicates important stress-response signals between cells. Taken together, our findings suggest that an active process of cell-to-cell ROS signaling, like the ROS wave, evolved before unicellular and multicellular organisms diverged. This mechanism could have communicated an environmental stress signal between cells and coordinated the acclimation response of cells living in a community. The finding of a signaling process, like the ROS wave, in mammalian cells further contributes to our understanding of different diseases and could impact the development of new drugs that target, for example cancer or heart disease.

Dendritic cells (DCs) have been shown to play a major role in oral tolerance and this function has been associated with their ability to produce anti-inflammatory cytokines and to induce suppressive T regulatory cells. Herein, we demonstrate that upon oral administration of Ag, lamina propia (LP) DCs engage specific T cells and acquire a novel mechanism by which they transfer tolerance against diverse T cell specificities. Indeed, when Ig-MOG carrying the myelin oligodendrocyte glycoprotein (MOG)35–55 epitope was orally administered into either T cell sufficient or deficient mice, only the T cell sufficient hosts yielded CD8α+ and CD8α− LP DCs that were able to transfer tolerance to a variety of MHC class II-restricted effector T cells. Surprisingly, these LP DCs up-regulated programmed cell death ligand 1 (PD-L1) during the initial interaction with MOG-specific T cells and utilized this inhibitory molecule to suppress activation of T cells regardless of Ag specificity. Furthermore, oral Ig-MOG was able to overcome experimental allergic encephalomyelitis (EAE) induced with central nervous system (CNS) homogenate, indicating that the DCs are able to modulate disease involving diverse T cell specificities. This previously unrecognized attribute potentiates DCs against autoimmunity.