Search

Resuscitation guidelines are developed and revised by medical societies throughout the world. These guidelines are increasingly based on evidence from preclinical and clinical research. The International Liaison Committee on Resuscitation reviews evidence for each resuscitation practice and provides summary consensus statements that inform resuscitation guideline committees. A similar process is used for different populations including neonatal, pediatric, and adult resuscitation. The NeoHeart 2020 Conference brought together experts in resuscitation to discuss recent evidence and guidelines for resuscitation practices. This review summarizes the main focus of discussion from this symposium.

Clinical trials of mesenchymal stem/stromal cell (MSC) therapy for bronchopulmonary dysplasia (BPD) are already underway. A thorough understanding of the preclinical work that underpins these trials is critical for neonatal practitioners to properly evaluate them. The more significant advances have been in investigating the mechanisms of action by which MSCs are thought to ameliorate BPD, and the recognition that this therapeutic effect is largely contained within the non-cellular exosome fraction of MSCs. In rodent hyperoxia models of BPD, MSCs have a pro-angiogenic effect mediated largely by vascular endothelial growth factor (VEGF) and shift the balance of endogenous lung cells from a pro-inflammatory to a pro-healing phenotype. MSC-derived exosomes can recapitulate these effects.

Inflammation can activate hematopoietic stem and progenitor cells (HSPCs) to proliferate and differentiate, signal the specification of HSPCs during embryonic development, and maintain adult HSPC homeostasis. Collins et al. review the role of inflammatory signaling in these diverse hematopoietic scenarios., Inflammation exerts multiple effects on the early hematopoietic compartment. Best studied is the role of proinflammatory cytokines in activating adult hematopoietic stem and progenitor cells to dynamically replenish myeloid lineage cells in a process known as emergency myelopoiesis. However, it is increasingly appreciated that the same proinflammatory signaling pathways are used in diverse hematopoietic scenarios. This review focuses on inflammatory signaling in the emergence of the definitive hematopoietic compartment during embryonic life, and tonic inflammatory signals derived from commensal microbiota in shaping the adult hematopoietic compartment in the absence of pathogenic insults. Insights into the unique and shared aspects of inflammatory signaling that regulate hematopoietic stem and progenitor cell function across the lifespan and health span of an individual will enable better diagnostic and therapeutic approaches to hematopoietic dysregulation and malignancies.

One in 10 newborns will be born before completion of 36 weeks’ gestation (premature birth). Infection and sepsis in preterm infants remain a significant clinical problem that represents a substantial financial burden on the healthcare system. Many factors predispose premature infants for having the greatest risk of developing and succumbing to infection as compared with all other age groups across the age spectrum. It is clear that the immune system of preterm infants exhibits distinct, rather than simply deficient, function as compared with more mature and older humans and that the immune function in preterm infants contributes to infection risk. While no single review can cover all aspects of immune function in this population, we will discuss key aspects of preterm neonatal innate and adaptive immune function that place them at high risk for developing infections and sepsis, as well as sepsis-associated morbidity and mortality.

Over the past several decades, bicarbonate therapy continues to be used routinely in the treatment of acute metabolic acidosis in critically ill neonates despite the lack of evidence for its effectiveness in the treatment of acid-base imbalance, and evidence indicating that it may be detrimental. Clinicians often feel compelled to use bicarbonate since acidosis implies a need for such therapy and thus the justification for its use is based on hearsay rather than science. This review summarizes the evidence and refutes the clinical practice of administering sodium bicarbonate to treat metabolic acidosis associated with several specific clinical syndromes in neonates.

Type 1 innate lymphocytes comprise two developmentally divergent lineages, type 1 helper innate lymphoid cells (hILC1s) and conventional NK cells (cNKs). All type 1 innate lymphocytes (ILCs) express the transcription factor T-bet, but cNKs additionally express Eomesodermin (Eomes). We show that deletion of Eomes alleles at the onset of type 1 ILC maturation using NKp46-Cre imposes a substantial block in cNK development. Formation of the entire lymphoid and nonlymphoid type 1 ILC compartment appears to require the semiredundant action of both T-bet and Eomes. To determine if Eomes is sufficient to redirect hILC1 development to a cNK fate, we generated transgenic mice that express Eomes when and where T-bet is expressed using Tbx21 locus control to drive expression of Eomes codons. Ectopic Eomes induces cNK-like properties across the lymphoid and nonlymphoid type 1 ILC compartments. Subsequent to their divergent lineage specification, hILC1s and cNKs thus possess substantial developmental plasticity.

Immaturity of the immune system of human fetuses and neonates is often invoked to explain their increased susceptibility to infection; however, the development of the fetal innate immune system in early life remains incompletely explored. We now show that the most mature NK cells found in adult (or postnatal) human circulation (CD94-CD16+) are absent during ontogeny. Human fetal NK cells were found to express the 2 signature T-box transcription factors essential for the development of all murine NK and NK-like cells, eomesodermin (Eomes) and T-bet. The single-cell pattern of Eomes and T-bet expression during ontogeny, however, revealed a stereotyped pattern of reciprocal dominance, with immature NK cells expressing higher amounts of Eomes and more mature NK cells marked by greater abundance of T-bet. We also observed a stereotyped pattern of tissue-specific NK cell maturation during human ontogeny, with fetal liver being more restrictive to NK cell maturity than fetal bone barrow, spleen, or lung. These results support the hypothesis that maturation of human NK cells has a discrete restriction until postnatal life, and provide a framework to better understand the increased susceptibility of fetuses and newborns to infection.

Summary T cell fate is associated with mutually exclusive expression of CD4 or CD8 in helper and cytotoxic T cells, respectively. How expression of one locus is temporally coordinated with repression of the other has been a long-standing enigma, though we know RUNX transcription factors activate the Cd8 locus, silence the Cd4 locus, and repress the Zbtb7b locus (encoding the transcription factor ThPOK), which is required for CD4 expression. Here we found that nuclear organization was altered by interplay among members of this transcription factor circuitry: RUNX binding mediated association of Cd4 and Cd8 whereas ThPOK binding kept the loci apart. Moreover, targeted deletions within Cd4 modulated CD8 expression and pericentromeric repositioning of Cd8. Communication between Cd4 and Cd8 thus appears to enable long-range epigenetic regulation to ensure that expression of one excludes the other in mature CD4 or CD8 single-positive (SP) cells., Graphical Abstract Highlights ► Association of Cd4 and Cd8 genes enables coordinate gene regulation ► Cd4 and Cd8 associate with one another in CD8-expressing cells ► RUNX transcription factor mediates association of Cd4 and Cd8 genes ► Targeted deletions within Cd4 modulate expression and nuclear location of Cd8

The stability of a lineage program (cellular memory) is dependent on mechanisms that epigenetically maintain active or repressed states of gene expression (transcriptional memory). Although epigenetic silencing of genes has been clearly demonstrated from yeast to mammals, heritable maintenance of active transcription has been less clearly defined. To investigate the potential role of active transcriptional memory during lineage diversification, we employed targeted mutation of a positive-acting cis element in the Cd4 locus to determine the impact on CD4 expression and the differentiation of CD4+ helper T cells in mice. We show that the proximal enhancer (E4P) of Cd4 is essential for CD4 expression in immature CD4+8+ thymocytes. Futhermore, its loss resulted in reduced and unstable expression of CD4 in mature T cells. However, if the enhancer was deleted after cells had already committed to the helper T-cell lineage, CD4 expression remained high and was stable upon cell division. “Active” histone modifications, once initiated by E4P, were also propagated independently of the enhancer. Thus, E4P is responsible for establishing an epigenetically inherited active Cd4 locus in the helper T-cell lineage. To our knowledge, this is the first genetic demonstration of active transcriptional memory in mammalian cells.

Recent research has uncovered complex transcription factor networks that control the processes of T-cell development and differentiation. RUNX (runt-related transcription factor) proteins are among the many factors that have crucial roles in these networks. In this Review, we examine the mechanisms by which RUNX complexes act together with other transcription factors, such as Th-POK (T-helper-inducing POZ/Kruppel-like factor) and GATA-binding protein 3 (GATA3) in determining the CD4/CD8 lineage choice of developing thymocytes. In addition, we discuss evidence indicating that RUNX complexes are also involved in the differentiation of effector T-cell subsets and that the molecular mechanisms by which RUNX proteins regulate T-cell fate decisions are conserved between the thymus and periphery.

CD43 is a highly glycosylated transmembrane protein that regulates T cell activation. CD43−/− T cells are hyperproliferative and the cytoplasmic tail of CD43 has been found to be sufficient to reconstitute wild-type proliferation levels, suggesting an intracellular mechanism. In this study, we report that upon TCR ligation CD43−/− T cells demonstrated no increase in tyrosine phosphorylation but a decreased calcium flux. Interestingly, CD43−/− T cells preferentially differentiated into Th2 cells in vitro, and CD43−/− T cells show increased GATA-3 translocation into the nucleus. In vivo, CD43−/− mice exhibited increased inflammation in two separate models of Th2-mediated allergic airway disease. In contrast, in Th1-mediated diabetes, nonobese diabetic CD43−/− mice did not significantly differ from wild-type mice in disease onset or progression. Th1-induced experimental autoimmune encephalomyelitis to MOG35–55 was also normal in the CD43−/− mice. Nonetheless, the CD43−/− mice produced more IL-5 when restimulated with MOG35–55 in vitro and demonstrated decreased delayed-type hypersensitivity responses. Together, these data demonstrate that although CD43−/− T cells preferentially differentiate into Th2 cells, this response is not sufficient to protect against Th1-mediated autoimmune responses.

How CD4+CD8+ thymocytes commit to CD4 helper versus CD8 cytotoxic lineages is a central unresolved question in developmental immunology. In this issue, Sarafova et al. (2005) show that engineering CD4 for shutoff immediately after positive selection misdirects cells to the cytotoxic lineage. The result highlights the distinction between positive selection and lineage commitment and provides new impetus for reexamining lineage models.