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Microbial exposures and sex hormones exert potent effects on autoimmune diseases, many of which are more prevalent in women. We demonstrate that early-life microbial exposures determine sex hormone levels and modify progression to autoimmunity in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). Colonization by commensal microbes elevated serum testosterone and protected NOD males from T1D. Transfer of gut microbiota from adult males to immature females altered the recipient's microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and robust T1D protection. These effects were dependent on androgen receptor activity. Thus, the commensal microbial community alters sex hormone levels and regulates autoimmune disease fate in individuals with high genetic risk.

Immunological memory specific to previously encountered antigens is a cardinal feature of adaptive lymphoid cells. However, it is unknown whether innate myeloid cells retain memory of prior antigenic stimulation and respond to it more vigorously on subsequent encounters. In this work, we show that murine monocytes and macrophages acquire memory specific to major histocompatibility complex I (MHC-I) antigens, and we identify A-type paired immunoglobulin-like receptors (PIR-As) as the MHC-I receptors necessary for the memory response. We demonstrate that deleting PIR-A in the recipient or blocking PIR-A binding to donor MHC-I molecules blocks memory and attenuates kidney and heart allograft rejection. Thus, innate myeloid cells acquire alloantigen-specific memory that can be targeted to improve transplant outcomes.

By functionally isolating stem cells (LSCs) from individuals with leukemia and parsing our their gene expression, Dick and his colleagues find that LSCs have heterogeneous surface markers and frequencies and possess a gene expression profile resembling that of normal hematopoietic stem cells. The gene expression program derived from LSCs could be a general predictor of disease outcome, stratifying risk for cytogenetically normal patients, which suggests that stemness underlies leukemia aggressiveness. Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying 'stemness' properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.

Background Synthetic human milk oligosaccharides (HMOs) are used to supplement infant formula despite limited understanding of their impact on the post-weaned developing gut microbiota. Here, we assess the influence of 0.5 g/L 2-fucosyllactose (2’FL) and 4.0 g/L pooled HMOs (pHMOs) on the composition and activity of cultured fecal-derived microbial communities from seven healthy young children. Results Exposure to pHMOs induced significant shifts in both the microbial community composition and metabolic output, including an increased abundance of several genera, notably Bacteroides , and the production of health-associated metabolites. In contrast, 2’FL alone did not lead to substantial changes in the communities. A total of 330 bacterial isolates, spanning 157 species, were cultured from these communities and individually evaluated for their responses to HMOs. Over 100 non- Bifidobacterium species showed enhanced growth upon pHMOs treatment and a high degree of intraspecies variation in HMO metabolism was observed. Conclusion Our study provides valuable insight into the health-enhancing properties of HMOs while highlighting the need for future research into the efficacy of incorporating individual structures into infant formula, particularly when aiming to modulate the gut microbiota. DLoTGpXbSBXfYGWsHwkdt7 Video Abstract

Graft failure in the transplantation of hematopoietic stem cells occurs despite donor-host genetic identity of human leukocyte antigens, suggesting that additional factors modulate engraftment. With the nobese diabetic (NOD)–severe combined immunodeficiency (SCID) xenotransplantation model, we found that the NOD background allowed better hematopoietic engraftment than did other strains with equivalent immunodeficiency-related mutations. We used positional genetics to characterize the molecular basis for this strain specificity and found that the NOD Sirpa allele conferred support for human hematopoiesis. NOD SIRP-α showed enhanced binding to the human CD47 ligand, and its expression on mouse macrophages was required for support of human hematopoiesis. Thus, we have identified Sirpa polymorphism as a potent genetic determinant of the engraftment of human hematopoietic stem cells.

Background The human gut microbiota is inoculated at birth and undergoes a process of assembly and diversification during the first few years of life. Studies in mice and humans have revealed associations between the early-life gut microbiome and future susceptibility to immune and metabolic diseases. To resolve microbe and host contributing factors to early-life development and to disease states requires experimental platforms that support reproducible, longitudinal, and high-content analyses. Results Here, we deployed a continuous single-stage chemostat culture model of the human distal gut to study gut microbiota from 18- to 24-month-old children integrating both culture-dependent and -independent methods. Chemostat cultures recapitulated multiple aspects of the fecal microbial ecosystem enabling investigation of relationships between bacterial strains and metabolic function, as well as a resource from which we isolated and curated a diverse library of early life bacterial strains. Conclusions We report the reproducible, longitudinal dynamics of early-life bacterial communities cultured in an advanced model of the human gut providing an experimental approach and a characterized bacterial resource to support future investigations of the human gut microbiota in early childhood.

With the advent of high through-put sequencing (HTS), the emerging science of metagenomics is transforming our understanding of the relationships of microbial communities with their environments. While metagenomics aims to catalogue the genes present in a sample through assessing which genes are actively expressed, metatranscriptomics can provide a mechanistic understanding of community inter-relationships. To achieve these goals, several challenges need to be addressed from sample preparation to sequence processing, statistical analysis and functional annotation. Here we use an inbred non-obese diabetic (NOD) mouse model in which germ-free animals were colonized with a defined mixture of eight commensal bacteria, to explore methods of RNA extraction and to develop a pipeline for the generation and analysis of metatranscriptomic data. Applying the Illumina HTS platform, we sequenced 12 NOD cecal samples prepared using multiple RNA-extraction protocols. The absence of a complete set of reference genomes necessitated a peptide-based search strategy. Up to 16% of sequence reads could be matched to a known bacterial gene. Phylogenetic analysis of the mapped ORFs revealed a distribution consistent with ribosomal RNA, the majority from Bacteroides or Clostridium species. To place these HTS data within a systems context, we mapped the relative abundance of corresponding Escherichia coli homologs onto metabolic and protein-protein interaction networks. These maps identified bacterial processes with components that were well-represented in the datasets. In summary this study highlights the potential of exploiting the economy of HTS platforms for metatranscriptomics.

Risk factors for most autoimmune diseases are multifactorial genetic variants modified by environmental risk factors. Type 1 diabetes and celiac disease share high-risk HLA haplotypes, and the prevalence of both diseases has increased in many regions during the past half century. Unknown environmental factors are suspected to have increased the disease penetrance. Celiac disease depends on immune responses to dietary gluten, whereas the environmental risk factors for type 1 diabetes are not yet clear. Here, we consider the shared heritable genetic factors and review evidence of the dietary and microbial exposures, particularly in early life, that might influence the pathogenesis of one or both diseases. A deeper mechanistic understanding of the environmental factors responsible for increased risk of these diseases should provide opportunities to manipulate exposure in children carrying defined risk markers and thus prevent and attenuate disease, as well as to identify new therapeutic strategies for patients. The rates of autoimmune disease are rising more rapidly than can be explained by changes in genetics. In this Focus Review, Verdu and Danska describe the dietary and microbial influences on type 1 diabetes and draw comparisons with celiac disease.

The identification of homotypic SLAMF7 interactions responsible for haematopoietic tumour cell phagocytosis by macrophages when the inhibitory receptor/ligand interaction of SIRPα/CD47 is blocked therapeutically. SLAMF7 receptor aids blockade therapy Phagocytosis of tumour cells has a critical role in cancer control, but the pro-phagocytic receptors responsible for this process are largely unknown. André Veillette and colleagues identify homotypic SLAMF7 interactions that are responsible for phagocytosis of haematopoietic tumour cells by macrophages when the inhibitory receptor–ligand interaction of CD47–SIRPα is blocked therapeutically. The authors suggest that the presence of SLAMF7 receptors on haematopoietic tumours could therefore be an important factor in blockade therapy. Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors 1 , 2 . Phagocytosis by macrophages plays a critical role in cancer control 3 , 4 , 5 , 6 . Therapeutic blockade of signal regulatory protein (SIRP)-α, an inhibitory receptor on macrophages, or of its ligand CD47 expressed on tumour cells, improves tumour cell elimination in vitro and in vivo 7 , 8 , 9 , 10 , suggesting that blockade of the SIRPα–CD47 checkpoint could be useful in treating human cancer 11 , 12 , 13 , 14 . However, the pro-phagocytic receptor(s) responsible for tumour cell phagocytosis is(are) largely unknown. Here we find that macrophages are much more efficient at phagocytosis of haematopoietic tumour cells, compared with non-haematopoietic tumour cells, in response to SIRPα–CD47 blockade. Using a mouse lacking the signalling lymphocytic activation molecule (SLAM) family of homotypic haematopoietic cell-specific receptors, we determined that phagocytosis of haematopoietic tumour cells during SIRPα–CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo . In both mouse and human cells, this function required a single SLAM family member, SLAMF7 (also known as CRACC, CS1, CD319), expressed on macrophages and tumour cell targets. In contrast to most SLAM receptor functions 15 , 16 , 17 , SLAMF7-mediated phagocytosis was independent of signalling lymphocyte activation molecule-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin Mac-1 (refs 18 , 19 , 20 ) and utilize signals involving immunoreceptor tyrosine-based activation motifs 21 , 22 . These findings elucidate the mechanism by which macrophages engulf and destroy haematopoietic tumour cells. They also reveal a novel SAP adaptor-independent function for a SLAM receptor. Lastly, they suggest that patients with tumours expressing SLAMF7 are more likely to respond to SIRPα–CD47 blockade therapy.