Pollinator-assisted plant phenotyping, selection, and breeding for crop resilience to abiotic stresses.

Food security is threatened by climate change, with heat and drought being the main stresses affecting crop physiology and ecosystem services, such as plant-pollinator interactions. We hypothesize that tracking and ranking pollinators' preferences for flowers under environmental pressure could be used as a marker of plant quality for agricultural breeding to increase crop stress tolerance. Despite increasing relevance of flowers as the most stress sensitive organs, phenotyping platforms aim at identifying traits of resilience by assessing the plant physiological status through remote sensing-assisted vegetative indexes, but find strong bottlenecks in quantifying flower traits and in accurate genotype-to-phenotype prediction. However, as the transport of photoassimilates from leaves (sources) to flowers (sinks) is reduced in low-resilient plants, flowers are better indicators than leaves of plant well-being. Indeed, the chemical composition and amount of pollen and nectar that flowers produce, which ultimately serve as food resources for pollinators, change in response to environmental cues. Therefore, pollinators' preferences could be used as a measure of functional source-to-sink relationships for breeding decisions. To achieve this challenging goal, we propose to develop a pollinator-assisted phenotyping and selection platform for automated quantification of Genotype × Environment × Pollinator interactions through an insect geo-positioning system. Pollinator-assisted selection can be validated by metabolic, transcriptomic, and ionomic traits, and mapping of candidate genes, linking floral and leaf traits, pollinator preferences, plant resilience, and crop productivity. This radical new approach can change the current paradigm of plant phenotyping and find new paths for crop redomestication and breeding assisted by ecological decisions.

Smart selection of soil microbes for resilient and sustainable viticulture.

The grapevine industry is of high economic importance in several countries worldwide. Its growing market demand led to an acceleration of the entire production processes, implying increasing use of water resources at the expense of environmental water balance and the hydrological cycle. Furthermore, in recent decades climate change and the consequent expansion of drought have further compromised water availability, making current agricultural systems even more fragile from ecological and economical perspectives. Consequently, farmers' income and welfare are increasingly unpredictable and unstable. Therefore, it is urgent to improve the resilience of vineyards, and of agro-ecosystems in general, by developing sustainable and environmentally friendly farming practices by more rational biological and natural resources use. The PRIMA project PROSIT addresses these challenges by characterizing and harnessing grapevine-associated microbiota to propose innovative and sustainable agronomic practices. PROSIT aims to determine the efficacy of natural microbiomes transferred from grapevines adapted to arid climate to commonly cultivated grapevine cultivars. In doing so it will test those natural microbiome effects on drought tolerance. This multidisciplinary project will utilize in vitro culture techniques, bioimaging, microbiological tests, metabolomics, metabarcoding and epigenetic analyses. These will be combined to shed light on molecular mechanisms triggered in plants by microbial associations upon water stress. To this end it is hoped that the project will serve as a blueprint not only for studies uncovering the microbiome role in drought stress in a wide range of species, but also for analyzing its effect on a wide range of stresses commonly encountered in modern agricultural systems.

Genome-wide association studies identify loci controlling specialized seed metabolites in Arabidopsis.

Plants synthesize specialized metabolites to facilitate environmental and ecological interactions. During evolution, plants diversified in their potential to synthesize these metabolites. Quantitative differences in metabolite levels of natural Arabidopsis (Arabidopsis thaliana) accessions can be employed to unravel the genetic basis for metabolic traits using genome-wide association studies (GWAS). Here, we performed metabolic GWAS on seeds of a panel of 315 A. thaliana natural accessions, including the reference genotypes C24 and Col-0, for polar and semi-polar seed metabolites using untargeted ultra-performance liquid chromatography-mass spectrometry. As a complementary approach, we performed quantitative trait locus (QTL) mapping of near-isogenic introgression lines between C24 and Col-0 for specific seed specialized metabolites. Besides common QTL between seeds and leaves, GWAS revealed seed-specific QTL for specialized metabolites, indicating differences in the genetic architecture of seeds and leaves. In seeds, aliphatic methylsulfinylalkyl and methylthioalkyl glucosinolates associated with the ALKENYL HYDROXYALKYL PRODUCING loci (GS-ALK and GS-OHP) on chromosome 4 containing alkenyl hydroxyalkyl producing 2 (AOP2) and 3 (AOP3) or with the GS-ELONG locus on chromosome 5 containing methylthioalkyl malate synthase (MAM1) and MAM3. We detected two unknown sulfur-containing compounds that were also mapped to these loci. In GWAS, some of the annotated flavonoids (kaempferol 3-O-rhamnoside-7-O-rhamnoside, quercetin 3-O-rhamnoside-7-O-rhamnoside) were mapped to transparent testa 7 (AT5G07990), encoding a cytochrome P450 75B1 monooxygenase. Three additional mass signals corresponding to quercetin-containing flavonols were mapped to UGT78D2 (AT5G17050). The association of the loci and associating metabolic features were functionally verified in knockdown mutant lines. By performing GWAS and QTL mapping, we were able to leverage variation of natural populations and parental lines to study seed specialized metabolism. The GWAS data set generated here is a high-quality resource that can be investigated in further studies.

Cross-Species Metabolomic Analyses in the Brassicaceae Reveals Common Responses to Ultraviolet-B Exposure.

Exposure to UV-B radiation, an intrinsic component of solar light, is detrimental to all living organisms as chromophore units of DNA, RNA and proteins readily absorb high-energy photons. Indirect damage to the same molecules and lipids is mediated by elevated reactive oxygen species (ROS) levels, a side effect of exposure to UV-B stress. To protect themselves from UV-B radiation, plants produce phytochemical sunscreens, among which flavonoids have shown to be particularly effective. The core aglycone of flavonoid molecules is subjected to chemical decoration, such as glycosylation and acylation, further improving sunscreen properties. In particular, acylation, which adds a phenolic ring to flavonoid molecules, enhances the spectral absorption of UV-A and UV-B rays, providing to this class of compounds exceptional shielding power. In this study, we comprehensively analyzed the responses to UV-B radiation in four Brassicaceae species, including Arabidopsis thaliana, Brassica napus, Brassica oleracea, and Brassica rapa. Our study revealed a complete reprogramming of the central metabolic pathway in response to UV-B radiation characterized by increased production of functional precursors of specialized metabolites with UV-B shielding properties, indicating a targeted effort of plant metabolism to provide increased protection. The analysis of specialized metabolites and transcripts revealed the activation of the phenylpropanoid-acetate pathway, leading to the production of specific classes of flavonoids and a cross-species increase in phenylacylated-flavonoid glucosides with synapoyl glycoside decorations. Interestingly, our analysis also revealed that acyltransferase genes of the class of serine carboxypeptidase-like (SCPLs) proteins are costitutively expressed, but downregulated in response to UV-B radiation, possibly independently of the ELONGATED HYPOCOTYL 5 (HY5) signaling pathway.

High-energy-level metabolism and transport occur at the transition from closed to open flowers.

During the maturation phase of flower development, the onset of anthesis visibly marks the transition from buds to open flowers, during which petals stretch out, nectar secretion commences, and pollination occurs. Analysis of the metabolic changes occurring during this developmental transition has primarily focused on specific classes of metabolites, such as pigments and scent emission, and far less on the whole network of primary and secondary metabolites. To investigate the metabolic changes occurring at anthesis, we performed multi-platform metabolomics alongside RNA sequencing in individual florets harvested from the main inflorescence of Arabidopsis (Arabidopsis thaliana) ecotype Col-0. To trace metabolic fluxes at the level of the whole inflorescence and individual florets, we further integrated these studies with radiolabeled experiments. These extensive analyses revealed high-energy-level metabolism and transport of carbohydrates and amino acids, supporting intense metabolic rearrangements occurring at the time of this floral transition. These comprehensive data are discussed in the context of our current understanding of the metabolic shifts underlying flower opening. We envision that this analysis will facilitate the introgression of floral metabolic traits promoting pollination in crop species for which a comprehensive knowledge of flower metabolism is still limited.

Outstanding questions in flower metabolism.

The great diversity of flowers, their color, odor, taste, and shape, is mostly a result of the metabolic processes that occur in this reproductive organ when the flower and its tissues develop, grow, and finally die. Some of these metabolites serve to advertise flowers to animal pollinators, other confer protection towards abiotic stresses, and a large proportion of the molecules of the central metabolic pathways have bioenergetic and signaling functions that support growth and the transition to fruits and seeds. Although recent studies have advanced our general understanding of flower metabolism, several questions still await an answer. Here, we have compiled a list of open questions on flower metabolism encompassing molecular aspects, as well as topics of relevance for agriculture and the ecosystem. These questions include the study of flower metabolism through development, the biochemistry of nectar and its relevance to promoting plant-pollinator interaction, recycling of metabolic resources after flowers whiter and die, as well as the manipulation of flower metabolism by pathogens. We hope with this review to stimulate discussion on the topic of flower metabolism and set a reference point to return to in the future when assessing progress in the field.

Pharyngeal Microbial Signatures Are Predictive of the Risk of Fungal Pneumonia in Hematologic Patients.

The ability to predict invasive fungal infections (IFI) in patients with hematological malignancies is fundamental for successful therapy. Although gut dysbiosis is known to occur in hematological patients, whether airway dysbiosis also contributes to the risk of IFI has not been investigated. Nasal and oropharyngeal swabs were collected for functional microbiota characterization in 173 patients with hematological malignancies recruited in a multicenter, prospective, observational study and stratified according to the risk of developing IFI. A lower microbial richness and evenness were found in the pharyngeal microbiota of high-risk patients that were associated with a distinct taxonomic and metabolic profile. A murine model of IFI provided biologic plausibility for the finding that loss of protective anaerobes, such as Clostridiales and Bacteroidetes, along with an apparent restricted availability of tryptophan, is causally linked to the risk of IFI in hematologic patients and indicates avenues for antimicrobial stewardship and metabolic reequilibrium in IFI.

Anakinra Activates Superoxide Dismutase 2 to Mitigate Inflammasome Activity.

Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.

Plant Single-Cell Metabolomics-Challenges and Perspectives.

Omics approaches for investigating biological systems were introduced in the mid-1990s and quickly consolidated to become a fundamental pillar of modern biology. The idea of measuring the whole complement of genes, transcripts, proteins, and metabolites has since become widespread and routinely adopted in the pursuit of an infinity of scientific questions. Incremental improvements over technical aspects such as sampling, sensitivity, cost, and throughput pushed even further the boundaries of what these techniques can achieve. In this context, single-cell genomics and transcriptomics quickly became a well-established tool to answer fundamental questions challenging to assess at a whole tissue level. Following a similar trend as the original development of these techniques, proteomics alternatives for single-cell exploration have become more accessible and reliable, whilst metabolomics lag behind the rest. This review summarizes state-of-the-art technologies for spatially resolved metabolomics analysis, as well as the challenges hindering the achievement of sensu stricto metabolome coverage at the single-cell level. Furthermore, we discuss several essential contributions to understanding plant single-cell metabolism, finishing with our opinion on near-future developments and relevant scientific questions that will hopefully be tackled by incorporating these new exciting technologies.

Flowers and climate change: a metabolic perspective.

Adverse climatic conditions at the time of flowering severely hinder crop yields and threaten the interactions between plants and their pollinators. These features depend on a common trait: the metabolism of flowers. In this Viewpoint article, we aim to provide insight into the metabolic changes that occur in flowers in response to changes in climate and emphasize that these changes severely impact the fitness of autogamous and allogamous species, plant-pollinator interactions, and overall ecosystem health. We review the biochemical processes that lead to failure of gamete development and to alterations of color, scent and nectar secretion. Then, making use of open access expression data, we examine the expression of genes that may drive these changes in response to heat and drought. Finally, we present measurements of metabolites from flowers exposed to a heat wave and discuss how the results of this short-term experiment may give rise to misleading conclusions regarding the positive effect of heat on flower fitness. We hope this article draws attention to this often-neglected dynamic and its important consequences.

Correction to: Cloning and characterization of a monoterpene synthase gene from flowers of Camelina sativa.

In the original publication, the order of figures and citations was incorrect. The corrections are listed below.

Cloning and characterization of a monoterpene synthase gene from flowers of Camelina sativa.

MAIN CONCLUSION: CsTPS1 encodes for a monoterpene synthase that contributes to the emission of a blend of volatile compounds emitted from flowers of Camelina sativa. The work describes the in vitro characterization of a monoterpene synthase and its regulatory region that we cloned from Camelina sativa (Camelina). Here, we named this gene as C. sativa terpene synthase 1 (CsTPS1). In vitro experiments performed with the CsTPS1 protein after expression and purification from Escherichia coli (E. coli) showed production of a blend of monoterpene volatile organic compounds, of which the emission was also detected in the floral bouquet of wild-type Camelina plants. Quantitative-PCR measurements revealed a high abundance of CsTPS1 transcripts in flowers and experiments performed with the GUS reporter showed high CsTPS1 expression in the pistil, in the cells of the wall of the ovary and in the stigma. Subcellular localization of the CsTPS1 protein was investigated with a GFP reporter construct that showed expression in plastids. The CsTPS1 gene identified in this study belongs to a mid-size family of 60 genes putatively codifying for TPS enzymes. This enlarged family of TPS genes suggests that Camelina has the structural framework for the production of terpenes and other secondary metabolites of relevance for the consumers.

The Mast Cell-Aryl Hydrocarbon Receptor Interplay at the Host-Microbe Interface.

Mast cells are increasingly being recognized as crucial cells in the response of the organism to environmental agents. Interestingly, the ability of mast cells to sense and respond to external cues is modulated by the microenvironment that surrounds mast cells and influences their differentiation. The scenario that is emerging unveils a delicate equilibrium that balances the effector functions of mast cells to guarantee host protection without compromising tissue homeostasis. Among the environmental components able to mold mast cells and fine-tune their effector functions, the microorganisms that colonize the human body, collectively known as microbiome, certainly play a key role. Indeed, microorganisms can regulate not only the survival, recruitment, and maturation of mast cells but also their activity by setting the threshold required for the exploitation of their different effector functions. Herein, we summarize the current knowledge about the mechanisms underlying the ability of the microorganisms to regulate mast cell physiology and discuss potential deviations that result in pathological consequences. We will discuss the pivotal role of the aryl hydrocarbon receptor in sensing the environment and shaping mast cell adaptation at the host-microbe interface.

Towards Targeting the Aryl Hydrocarbon Receptor in Cystic Fibrosis.

Tryptophan (trp) metabolism is an important regulatory component of gut mucosal homeostasis and the microbiome. Metabolic pathways targeting the trp can lead to a myriad of metabolites, of both host and microbial origins, some of which act as endogenous low-affinity ligands for the aryl hydrocarbon receptor (AhR), a cytosolic, ligand-operated transcription factor that is involved in many biological processes, including development, cellular differentiation and proliferation, xenobiotic metabolism, and the immune response. Low-level activation of AhR by endogenous ligands is beneficial in the maintenance of immune health and intestinal homeostasis. We have defined a functional node whereby certain bacteria species contribute to host/microbial symbiosis and mucosal homeostasis. A microbial trp metabolic pathway leading to the production of indole-3-aldehyde (3-IAld) by lactobacilli provided epithelial protection while inducing antifungal resistance via the AhR/IL-22 axis. In this review, we highlight the role of AhR in inflammatory lung diseases and discuss the possible therapeutic use of AhR ligands in cystic fibrosis.

Autophagy and LAP in the Fight against Fungal Infections: Regulation and Therapeutics.

Phagocytes fight fungi using canonical and noncanonical, also called LC3-associated phagocytosis (LAP), autophagy pathways. However, the outcomes of autophagy/LAP in shaping host immune responses appear to greatly vary depending on fungal species and cell types. By allowing efficient pathogen clearance and/or degradation of inflammatory mediators, autophagy proteins play a broad role in cellular and immune homeostasis during fungal infections. Indeed, defects in autophagic machinery have been linked with aberrant host defense and inflammatory states. Thus, understanding the molecular mechanisms underlying the relationship between the different forms of autophagy may offer a way to identify drugable molecular signatures discriminating between selective recognition of cargo and host protection. In this regard, IFN-γ and anakinra are teaching examples of successful antifungal agents that target the autophagy machinery. This article provides an overview of the role of autophagy/LAP in response to fungi and in their infections, regulation, and therapeutic exploitation.

The MYB36 transcription factor orchestrates Casparian strip formation.

The endodermis in roots acts as a selectivity filter for nutrient and water transport essential for growth and development. This selectivity is enabled by the formation of lignin-based Casparian strips. Casparian strip formation is initiated by the localization of the Casparian strip domain proteins (CASPs) in the plasma membrane, at the site where the Casparian strip will form. Localized CASPs recruit Peroxidase 64 (PER64), a Respiratory Burst Oxidase Homolog F, and Enhanced Suberin 1 (ESB1), a dirigent-like protein, to assemble the lignin polymerization machinery. However, the factors that control both expression of the genes encoding this biosynthetic machinery and its localization to the Casparian strip formation site remain unknown. Here, we identify the transcription factor, MYB36, essential for Casparian strip formation. MYB36 directly and positively regulates the expression of the Casparian strip genes CASP1, PER64, and ESB1. Casparian strips are absent in plants lacking a functional MYB36 and are replaced by ectopic lignin-like material in the corners of endodermal cells. The barrier function of Casparian strips in these plants is also disrupted. Significantly, ectopic expression of MYB36 in the cortex is sufficient to reprogram these cells to start expressing CASP1-GFP, correctly localize the CASP1-GFP protein to form a Casparian strip domain, and deposit a Casparian strip-like structure in the cell wall at this location. These results demonstrate that MYB36 is controlling expression of the machinery required to locally polymerize lignin in a fine band in the cell wall for the formation of the Casparian strip.

Tissue-specific production of limonene in Camelina sativa with the Arabidopsis promoters of genes BANYULS and FRUITFULL.

MAIN CONCLUSION: Arabidopsis promoters of genes BANYULS and FRUITFULL are transcribed in Camelina. They triggered the transcription of limonene synthase and induced higher limonene production in seeds and fruits than CaMV 35S promoter. Camelina sativa (Camelina) is an oilseed crop of relevance for the production of biofuels and the plant has been target of a recent and intense program of genetic manipulation aimed to increase performance, seed yield and to modify the fatty acid composition of the oil. Here, we have explored the performance of two Arabidopsis thaliana (Arabidopsis) promoters in triggering transgene expression in Camelina. The promoters of two genes BANYULS (AtBAN pro ) and FRUITFULL (AtFUL pro ), which are expressed in seed coat and valves of Arabidopsis, respectively, have been chosen to induce the expression of limonene synthase (LS) from Citrus limon. In addition, the constitutive CaMV 35S promoter was utilized to overexpress LS in Camelina . The results of experiments revealed that AtBAN pro and AtFUL pro are actively transcribed in Camelina where they also retain specificity of expression in seeds and valves as previously observed in Arabidopsis. LS induced by AtBAN pro and AtFUL pro leads to higher limonene production in seeds and fruits than when the CaMV 35S was used to trigger the expression. In conclusion, the results of experiments indicate that AtBAN pro and AtFUL pro can be successfully utilized to induce the expression of the transgenes of interest in seeds and fruits of Camelina.

Hypoxia promotes danger-mediated inflammation via receptor for advanced glycation end products in cystic fibrosis.

RATIONALE: Hypoxia regulates the inflammatory-antiinflammatory balance by the receptor for advanced glycation end products (RAGE), a versatile sensor of damage-associated molecular patterns. The multiligand nature of RAGE places this receptor in the midst of chronic inflammatory diseases. OBJECTIVES: To characterize the impact of the hypoxia-RAGE pathway on pathogenic airway inflammation preventing effective pathogen clearance in cystic fibrosis (CF) and elucidate the potential role of this danger signal in pathogenesis and therapy of lung inflammation. METHODS: We used in vivo and in vitro models to study the impact of hypoxia on RAGE expression and activity in human and murine CF, the nature of the RAGE ligand, and the impact of RAGE on lung inflammation and antimicrobial resistance in fungal and bacterial pneumonia. MEASUREMENTS AND MAIN RESULTS: Sustained expression of RAGE and its ligand S100B was observed in murine lung and human epithelial cells and exerted a proximal role in promoting inflammation in murine and human CF, as revealed by functional studies and analysis of the genetic variability of AGER in patients with CF. Both hypoxia and infections contributed to the sustained activation of the S100B-RAGE pathway, being RAGE up-regulated by hypoxia and S100B by infection by Toll-like receptors. Inhibiting the RAGE pathway in vivo with soluble (s) RAGE reduced pathogen load and inflammation in experimental CF, whereas sRAGE production was defective in patients with CF. CONCLUSIONS: A causal link between hyperactivation of RAGE and inflammation in CF has been observed, such that targeting pathogenic inflammation alleviated inflammation in CF and measurement of sRAGE levels could be a useful biomarker for RAGE-dependent inflammation in patients with CF.

Biochemical characterization of Euphorbia resinifera floral cyathia.

Euphorbia resinifera O. Berg is a plant endemic to the Northern and Central regions of Morocco known since the ancient Roman and Greek times for secreting a poisonous latex containing resiniferatoxin. However, E. resinifera pseudo-inflorescences called cyathia are devoid of laticifers and, therefore, do not secrete latex. Instead, they exudate nectar that local honey bees collect and craft into honey. Honey and cyathium water extracts find a broad range of applications in the traditional medicine of Northern Africa as ointments and water decoctions. Moreover, E. resinifera monofloral honey has received the Protected Geographic Indication certification for its outstanding qualities. Given the relevance of E. resinifera cyathia for bee nutrition, honey production, and the health benefit of cyathium-derived products, this study aimed to screen metabolites synthesized and accumulated in its pseudo-inflorescences. Our analyses revealed that E. resinifera cyathia accumulate primary metabolites in considerable abundance, including hexoses, amino acids and vitamins that honey bees may collect from nectar and craft into honey. Cyathia also synthesize volatile organic compounds of the class of benzenoids and terpenes, which are emitted by flowers pollinated by honey bees and bumblebees. Many specialized metabolites, including carotenoids, flavonoids, and polyamines, were also detected, which, while protecting the reproductive organs against abiotic stresses, also confer antioxidant properties to water decoctions. In conclusion, our analyses revealed that E. resinifera cyathia are a great source of antioxidant molecules and a good food source for the local foraging honeybees, revealing the central role of the flowers from this species in mediating interactions with local pollinators and the conferral of medicinal properties to plant extracts.

Grafted Sertoli Cells Exert Immunomodulatory Non-Immunosuppressive Effects in Preclinical Models of Infection and Cancer.

The Sertoli cells (SeCs) of the seminiferous tubules secrete a multitude of immunoregulatory and trophic factors to provide immune protection and assist in the orderly development of germ cells. Grafts of naked or encapsulated SeCs have been proved to represent an interesting therapeutic option in a plethora of experimental models of diseases. However, whether SeCs have immunosuppressive or immunomodulatory effects, which is imperative for their clinical translatability, has not been demonstrated. We directly assessed the immunopotential of intraperitoneally grafted microencapsulated porcine SeCs (MC-SeCs) in murine models of fungal infection (Aspergillus fumigatus or Candida albicans) or cancer (Lewis lung carcinoma/LLC or B16 melanoma cells). We found that MC-SeCs (i) provide antifungal resistance with minimum inflammatory pathology through the activation of the tolerogenic aryl hydrocarbon receptor/indoleamine 2,3-dioxygenase pathway; (ii) do not affect tumor growth in vivo; and (iii) reduce the LLC cell metastatic cancer spread associated with restricted Vegfr2 expression in primary tumors. Our results point to the fine immunoregulation of SeCs in the relative absence of overt immunosuppression in both infection and cancer conditions, providing additional support for the potential therapeutic use of SeC grafts in human patients.