Tissue resident memory T cells (TRM) maintain immunity in diverse sites as determined in mouse models, while their establishment and role in human tissues has been difficult to assess. Here, we investigated human lung TRM generation, maintenance and function in airway samples obtained longitudinally from HLA-disparate lung transplant recipients, where donor and recipient T cells could be localized and tracked over time. Donor T cells persist specifically in the lungs (and not blood) of transplant recipients and express high levels of TRM signature markers including CD69, CD103, and CD49a, while lung-infiltrating recipient T cells gradually acquire TRM phenotypes over months in vivo. Single cell transcriptome profiling of airway T cells reveals that donor T cells comprise two TRM-like subsets with varying levels of expression of TRM-associated genes while recipient T cells comprised non-TRM and similar TRM-like subpopulations, suggesting de novo TRM generation. Transplant recipients exhibiting higher frequencies of persisting donor TRM experienced fewer adverse clinical events such as primary graft dysfunction and acute cellular rejection compared to recipients with low donor TRM persistence, suggesting that monitoring TRM dynamics could be clinically informative. Together, our results provide novel spatial and temporal insights into how human TRM develop, function, persist, and impact tissue integrity within the complexities of lung transplantation.

Orthostatic hypotension (OH) is the failure of cardiovascular reflexes to maintain blood pressure on standing from a supine or sitting position. Although OH may cause symptoms of dizziness or syncope, asymptomatic OH (AOH) is far more common and is an independent risk factor for mortality and cardiovascular disease (CVD). The prevalence of AOH increases with age, the presence of hypertension or diabetes and the use of antihypertensive or other medications. The implications of AOH for the treatment of CVD and hypertension are not well defined. This review provides an overview of the current information on this topic and recommends the more frequent assessment of OH in clinical practice and in future clinical trials.

The suprachiasmatic nucleus (SCN) orchestrates synchrony among many peripheral oscillators and is required for circadian rhythms of locomotor activity and many physiological processes. However, the unique effects of methamphetamine (MAP) on circadian behavior suggest the presence of an SCN-independent, methamphetamine-sensitive circadian oscillator (MASCO). Substantial data collected using rat models show that chronic methamphetamine dramatically lengthens circadian period of locomotor activity rhythms and induces rhythms in animals lacking an SCN. However, the anatomical substrate and the molecular components of the MASCO are unknown. The response to MAP is less well studied in mice, a model that would provide the genetic tools to probe the molecular components of this extra-SCN oscillator. The authors tested the effects of chronic MAP on 2 strains of intact and SCN-lesioned mice in constant dark and constant light. Furthermore, they applied various MAP availability schedules to SCN-lesioned mice to confirm the circadian nature of the underlying oscillator. The results indicate that this oscillator has circadian properties. In intact mice, the MASCO interacts with the SCN in a manner that is strain, sex, and dose dependent. In SCN-lesioned mice, it induces robust free-running locomotor rhythmicity, which persists for up to 14 cycles after methamphetamine is withdrawn. In the future, localization of the MASCO and characterization of its underlying molecular mechanism, as well as its interactions with other oscillators in the body, will be essential to a complete understanding of the organization of the mammalian circadian system.

Bone morphogenetic protein (BMP) signaling is an important regulator of hematovascular development. However, the progenitor population that responds to BMP signaling is undefined, and the relative role of downstream mediators including Smad1 is unclear. We find that Smad1 shows a distinctive expression profile as embryonic stem (ES) cells undergo differentiation in the embryoid body (EB) system, with peak levels in cell populations enriched for the hemangioblast. To test the functional relevance of this observation, we generated an ES cell line that allows temporal control of ectopic Smad1 expression. Continuous expression of Smad1 from day 2 of EB culture does not disturb hematopoiesis, according to colony assays. In contrast, a pulse of Smad1 expression exclusively between day 2 and day 2.25 expands the population of progenitors for primitive erythroblasts and other hematopoietic lineages. This effect correlates with increased levels of transcripts encoding markers for the hemangioblast, including Runx1, Scl, and Gata2. Indeed, the pulse of Smad1 induction also expands the blast colonyforming cell (BL-CFC) population at a level that is fully sufficient to explain subsequent increases in hematopoiesis. Our data demonstrate that Smad1 expression is sufficient to expand the number of cells that commit to hemangioblast fate. IntroductionThe progenitors that generate the early hematovascular system are derived from ventral mesoderm, which in mammals contributes to the yolk sac primitive blood lineage and associated vasculature. 1 The bone morphogenetic protein (BMP) signaling pathway is an essential regulator of the process by which mesoderm acquires ventral character. 2 Thus, ectopic activation of BMP signaling expands ventral mesoderm derivatives including increased numbers of embryonic hematopoietic cells, whereas inhibition of the pathway causes a corresponding loss in hematopoiesis. Genetic loss-of-function experiments in mice and fish have confirmed the conserved requirement for BMPs and downstream signaling components for the generation of blood cells. [3][4][5] However, because the pathway is essential first for the formation of normal ventral mesoderm, it has been more difficult to define regulatory functions that act on the subsequent commitment steps of mesoderm toward a hematopoietic fate. BMPs can influence hematopoietic progenitors in vitro, 6,7 but whether this reflects the normal process of stem cell commitment during embryogenesis is less clear.The Smads comprise a family of transcriptional cofactors that specifically transduce activated TGF-␤/BMP signals. 8 Smads 1, 5, and 8 constitute the receptor-activated Smads (R-Smads) that on phosphorylation by a type I BMP receptor bind the co-Smad4, common to all TGF-␤/BMP pathways, to form heteromeric protein complexes. These R-Smad/co-Smad complexes translocate to the nucleus and cooperate with other transcription factors to modulate target gene expression. Mice deficient for Smad1 or Smad5 display varying degrees of defects in hematopoietic and vascula...