Developmental hematopoiesis: innate programming of αβ T cells.

Meeting summary: International Symposium and Workshop on Hematopoietic Stem Cells V, University of Tübingen, Germany, September 16–18, 2004

The arcuate nucleus of the hypothalamus (ARC) is central in the neuronal regulation of fertility and reproduction through translating gonadal steroid hormone cues into the GnRH signaling pathway in the brain. Evidence suggests that circulating gonadal steroids play an important role in modulating female reproduction via kisspeptin and γ-aminobutyric acid (GABA) neurons in the ARC in both development and adulthood. However, the temporal onset of these ARC neurons' sensitivity to gonadal steroids is unknown. Using RNAscope® in situ hybridization, we localized androgen receptor (Ar), estrogen receptor alpha (Esr1), and progesterone receptor (Pgr) expression in ARC kisspeptin or GABA neurons of female mice at postnatal day (P)4, P8, P12, P20, and P60. A probe that binds to kiss1 mRNA or vGat mRNA was used to produce signal in kisspeptin or GABA neurons, respectively. In adult, we identified that the vast majority of kisspeptin neurons coexpressed Esr1 (95%) and Pgr (93%), while a smaller proportion coexpressed Ar (66%). Similar proportions of Ar- or Esr1-positive kisspeptin neurons were seen from P4, suggesting that kisspeptin neurons develop adult-like sensitivity to androgen and estrogen in early postnatal life. In contrast, the proportion of Pgr-positive kisspeptin cells in early life was significantly lower than in adulthood, suggesting that progesterone sensitivity develops over time in the ARC kisspeptin population. ARC GABA neurons also colocalized with Ar (70%), Esr1 (64%), or Pgr (85%) in adulthood. GABA neurons continuously expressed Esr1 or Pgr from the postnatal stages to adulthood, while the proportion of Ar-positive GABA neurons gradually increased from P4 (24%) to P20 (59%). These results suggest that while ARC GABA neurons can respond to circulating estrogen and progesterone from early postnatal ages, this same population may become more sensitive to androgens during later postnatal life. Our findings identified the expression patterns of Ar, Esr1, and Pgr by ARC kisspeptin and GABA neurons during early postnatal life. These data provide the understanding for the hormone sensitivity of these populations during early postnatal life, the critical time for the formation and regulation of female reproductive physiology.Esr1 (95%) and Pgr (93%), while a smaller proportion coexpressed Ar (66%). Similar proportions of Ar- or Esr1-positive kisspeptin neurons were seen from P4, suggesting that kisspeptin neurons develop adult-like sensitivity to androgen and estrogen in early postnatal life. In contrast, the proportion of Pgr-positive kisspeptin cells in early life was significantly lower than in adulthood, suggesting that progesterone sensitivity develops over time in the ARC kisspeptin population. ARC GABA neurons also colocalized with Ar (70%), Esr1 (64%), or Pgr (85%) in adulthood. GABA neurons continuously expressed Esr1 or Pgr from the postnatal stages to adulthood, while the proportion of Ar-positive GABA neurons gradually increased from P4 (24%) to P20 (59%). These results suggest that while ARC GABA neurons can respond to circulating estrogen and progesterone from early postnatal ages, this same population may become more sensitive to androgens during later postnatal life. Our findings identified the expression patterns of Ar, Esr1, and Pgr by ARC kisspeptin and GABA neurons during early postnatal life. These data provide the understanding for the hormone sensitivity of these populations during early postnatal life, the critical time for the formation and regulation of female reproductive physiology.

Changes in the frequencies of human hematopoietic stem and progenitor cells with age and site

Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging

Fetal and adult progenitors give rise to unique populations of CD8+ T cells

Perturbations of the mucosal immune system and the microbiota can lead to allergic disorders with a lifelong impact. With up to 90% of cases diagnosed by age 6, atopic dermatitis represents a unique allergic disorder during early life. Diagnosis of atopic dermatitis is associated with an increased risk for other allergic disorders throughout life. The opportunistic fungal species Candida albicans is often found as part of a dysbiotic microbiota and its presence is associated with increased risk of atopy. While adult mice are unable to be stably colonized with C. albicans without the use of antibiotics, we have found that mice exposed to C. albicans prior to weaning maintain long term colonization in the gut and on the skin. In mice colonized in early life with C. albicans in the GI tract, FoxP3+ T cells were significantly decreased post-weaning in the mesenteric lymph node as well as in the small intestine and colon lamina propria. Colonization by C. albicans resulted in an increased Th17 response, with increased RORγt+ and c-Maf+ T cells in the colon lamina propria. In a clinical observation study, we found C. albicans colonization in the intestine of prematurely born infants, suggesting colonization of the human GI tract with C. albicans may frequently occur. As the microbiota develops with age, the presence of C. albicans may impact the normal course of increasing complexity and diversity in this ecosystem. The establishment of regulatory T cells in early life is vital to maintaining tolerance to commensal organisms throughout life; this disruption in regulatory T cells potentially links colonization by C. albicans to the development of atopy and allergic responses. Supported by grants from Mayo Clinic Center for Individualized Medicine

Terminal differentiation induction as DNA damage response in hematopoietic stem cells by GADD45A.

Developmental hematopoiesis is an exciting multi-disciplinary field at the crossroads of developmental biology, hematopoiesis, stem cell biology and genetics. This field began nearly a century ago with detailed observations on the formation of the first blood cells, the primitive erythrocytes, in

Endothelial Cell-Selective Adhesion Molecule (ESAM) Is Required for the Ontogeny of Definitive Hematopoietic System in Mice

Neonates often develop poor immunity against intracellular pathogens. Because CD8+ T cells are essential for eliminating infectious agents, it is crucial to understand why they behave differently in early life. Previous studies in mice have demonstrated that neonatal CD8+ T cells fail to form memory because of an intrinsic propensity to differentiate into short-lived effectors. However, the underlying mechanisms remain undefined. We now show that neonatal CD8+ T cells exhibit higher glycolytic activity than adult CD8+ T cells postinfection, which may be due to age-related differences in Lin28b expression. Importantly, when glycolysis is pharmacologically inhibited, the impaired formation of neonatal memory CD8+ T cells can be restored. Collectively, these data suggest that neonatal CD8+ T cells are inherently biased toward undergoing glycolytic metabolism postinfection, which compromises their ability to develop into memory CD8+ T cells in early life.

Pbx1 Regulates Self-Renewal of Long-Term Hematopoietic Stem Cells by Maintaining Their Quiescence

Distinct Roles for Matrix Metalloproteinases 2 and 9 in Embryonic Hematopoietic Stem Cell Emergence, Migration, and Niche Colonization.

Neonates often generate incomplete immunity against intracellular pathogens, although the mechanism of this defect is poorly understood. An important question is whether the impaired development of memory CD8+ T cells in neonates is due to an immature priming environment or lymphocyte-intrinsic defects. In this article, we show that neonatal and adult CD8+ T cells adopted different fates when responding to equal amounts of stimulation in the same host. Whereas adult CD8+ T cells differentiated into a heterogeneous pool of effector and memory cells, neonatal CD8+ T cells preferentially gave rise to short-lived effector cells and exhibited a distinct gene expression profile. Surprisingly, impaired neonatal memory formation was not due to a lack of responsiveness, but instead because neonatal CD8+ T cells expanded more rapidly than adult cells and quickly became terminally differentiated. Collectively, these findings demonstrate that neonatal CD8+ T cells exhibit an imbalance in effector and memory CD8+ T cell differentiation, which impairs the formation of memory CD8+ T cells in early life.

Review of: "Lin28b specifies an innate-like lineage of CD8+ T cells in early life"

Compendia of large-scale datasets made available in public repositories provide an opportunity to identify and fill gaps in biomedical knowledge. But first, these data need to be made readily accessible to research investigators for interpretation. Here we make available a collection of transcriptome datasets to investigate the functional programming of human hematopoietic cells in early life. Thirty two datasets were retrieved from the NCBI Gene Expression Omnibus (GEO) and loaded in a custom web application called the Gene Expression Browser (GXB), which was designed for interactive query and visualization of integrated large-scale data. Quality control checks were performed. Multiple sample groupings and gene rank lists were created allowing users to reveal age-related differences in transcriptome profiles, changes in the gene expression of neonatal hematopoietic cells to a variety of immune stimulators and modulators, as well as during cell differentiation. Available demographic, clinical, and cell phenotypic information can be overlaid with the gene expression data and used to sort samples. Web links to customized graphical views can be generated and subsequently inserted in manuscripts to report novel findings. GXB also enables browsing of a single gene across projects, thereby providing new perspectives on age- and developmental stage-specific expression of a given gene across the human hematopoietic system. This dataset collection is available at: http://developmentalimmunology.gxbsidra.org/dm3/geneBrowser/list.