Group 2 innate lymphoid cells (ILC2s) promote type 2 cytokine-dependent immunity, inflammation, and tissue repair. Although epithelial cell-derived cytokines regulate ILC2 effector functions, the ...pathways that control the in vivo migration of ILC2s into inflamed tissues remain poorly understood. Here, we provide the first demonstration that expression of the prostaglandin D2 (PGD2) receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) regulates the in vivo accumulation of ILC2s in the lung. Although a significant proportion of ILC2s isolated from healthy human peripheral blood expressed CRTH2, a smaller proportion of ILC2s isolated from nondiseased human lung expressed CRTH2, suggesting that dynamic regulation of CRTH2 expression might be associated with the migration of ILC2s into tissues. Consistent with this, murine ILC2s expressed CRTH2, migrated toward PGD2 in vitro, and accumulated in the lung in response to PGD2 in vivo. Furthermore, mice deficient in CRTH2 exhibited reduced ILC2 responses and inflammation in a murine model of helminth-induced pulmonary type 2 inflammation. Critically, adoptive transfer of CRTH2-sufficient ILC2s restored pulmonary inflammation in CRTH2-deficient mice. Together, these data identify a role for the PGD2-CRTH2 pathway in regulating the in vivo accumulation of ILC2s and the development of type 2 inflammation in the lung.
Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by ...single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.
The extent to which tissue-specific viral infections generate memory T cells specifically adapted to and maintained within the target infection site is unknown. Here, we show that respiratory ...virus-specific memory T cells in mice and humans are generated and maintained in compartmentalized niches in lungs, distinct from populations in lymphoid tissue or circulation. Using a polyclonal mouse model of influenza infection combined with an in vivo antibody labeling approach and confocal imaging, we identify a spatially distinct niche in the lung where influenza-specific T-cell responses are expanded and maintained long term as tissue-resident memory (T(RM)) CD4 and CD8 T cells. Lung T(RM) are further distinguished from circulating memory subsets in lung and spleen based on CD69 expression and persistence independent of lymphoid stores. In humans, influenza-specific T cells are enriched within the lung T(RM) subset, whereas memory CD8 T cells specific for the systemic virus cytomegalovirus are distributed in both lung and spleen, suggesting that the site of infection affects T(RM) generation. Our findings reveal a precise spatial organization to virus-specific T-cell memory, determined by the site of the initial infection, with important implications for the development of targeted strategies to boost immunity at appropriate tissue sites.
Measurement of interseismic strain along subduction zones reveals the location of both locked asperities, which might rupture during megathrust earthquakes, and creeping zones, which tend to arrest ...such seismic ruptures. The heterogeneous pattern of interseismic coupling presumably relates to spatial variations of frictional properties along the subduction interface and may also show up in the fore‐arc morphology. To investigate this hypothesis, we compiled information on the extent of earthquake ruptures for the last 500 years and uplift rates derived from dated marine terraces along the South American coastline from central Peru to southern Chile. We additionally calculated a new interseismic coupling model for that same area based on a compilation of GPS data. We show that the coastline geometry, characterized by the distance between the coast and the trench; the latitudinal variations of long‐term uplift rates; and the spatial pattern of interseismic coupling are correlated. Zones of faster and long‐term permanent coastal uplift, evidenced by uplifted marine terraces, coincide with peninsulas and also with areas of creep on the megathrust where slip is mostly aseismic and tend to arrest seismic ruptures. We conclude that spatial variations of frictional properties along the megathrust dictate the tectono‐geomorphological evolution of the coastal zone and the extent of seismic ruptures along strike.
Key Points
Peninsulas are seismic barriers and show locally high Quaternary uplift rates (>0.4 m/ka)
They tend to form above aseismically sliding areas and are permanent over multiple seismic cycles
These dynamic features reflect anelastic deformation of the fore arc in response to the subduction seismic cycle
Organ donors are sources of physiologically healthy organs and tissues for life‐saving transplantation, and have been recently used for human immunology studies which are typically confined to the ...sampling of peripheral blood. Donors comprise a diverse population with different causes of death and clinical outcomes during hospitalization, and the effects of such variations on immune parameters in blood and tissues are not known. We present here a coordinate analysis of innate and adaptive immune components in blood, lymphoid (bone marrow, spleen, lymph nodes), and mucosal (lungs, intestines) sites from a population of brain‐dead organ donors (2 months‐93 years; n = 291) across eight clinical parameters. Overall, the blood of donors exhibited similar monocyte and lymphocyte content and low serum levels of pro‐inflammatory cytokines as healthy controls; however, donor blood had increased neutrophils and serum levels of IL‐8, IL‐6, and MCP‐1 which varied with cause of death. In tissues, the frequency and composition of monocytes, neutrophils, B lymphocytes and T cell subsets in lymphoid or mucosal sites did not vary with clinical state, and was similar in donors independent of the extent of clinical complications. Our results reveal that organ donors maintain tissue homeostasis, and are a valuable resource for fundamental studies in human immunology.
Organ donor tissue provides a valuable research resource for studying human tissue homeostasis, revealing stable frequencies of innate and adaptive immune cell populations in mucosal and lymphoid sites across eight clinical variables and despite alterations in circulation.
Phonons of the anomalous element cerium Krisch, Michael; Farber, D.L; Xu, R ...
Proceedings of the National Academy of Sciences - PNAS,
06/2011, Letnik:
108, Številka:
23
Journal Article
Recenzirano
Odprti dostop
Many physical and chemical properties of the light rare-earths and actinides are governed by the active role of f electrons, and despite intensive efforts the details of the mechanisms of phase ...stability and transformation are not fully understood. A prominent example which has attracted a lot of interest, both experimentally and theoretically over the years is the isostructural γ - α transition in cerium. We have determined by inelastic X-ray scattering, the complete phonon dispersion scheme of elemental cerium across the γ rightward arrow α transition, and compared it with theoretical results using ab initio lattice dynamics. Several phonon branches show strong changes in the dispersion shape, indicating large modifications in the interactions between phonons and conduction electrons. This is reflected as well by the lattice Grüneisen parameters, particularly around the X point. We derive a vibrational entropy change Formula , illustrating the importance of the lattice contribution to the transition. Additionally, we compare first principles calculations with the experiments to shed light on the mechanism underlying the isostructural volume collapse in cerium under pressure.
Toll-like receptors (TLRs) and proteinase-activated receptors (PARs) function as innate immune biosensors in mucosal epithelial cells (ECs). We previously reported the functional and physical ...interactions between TLR4 and PAR(2). We have extended these findings herein by showing the cooperation between PAR(2) and TLR2, TLR3, or TLR4 for activation of nuclear factor-kappaB-dependent signaling in mucosal EC lines. In contrast, activation of PAR(2) negatively regulated TLR3-dependent antiviral pathway, blunting the expression of TLR3/interferon regulatory factor-3 (IRF-3)-driven genes, as well as activation of IRF-3 and STAT1. Consistent with these in vitro observations, PAR(2)(-/-) and TLR4(-/-) mice, which were refractory to footpad edema induced by PAR(2) agonist peptide, were protected from mouse-adapted H1N1 influenza A virus-induced lethality when compared to wild-type (WT) mice. These data support and extend our recently described, novel model of PAR(2)-TLR4 "receptor cooperativity" and highlight the complexity of signaling integration between heterologous innate immune biosensors.
In this issue, Ayasoufi et al (page 2008) provide novel evidence that depletion‐resistant CD4 T cells migrate to the thymus and potentiate thymopoiesis, thereby providing a link between the two ...well‐established T cell reconstitution pathways.
T‐cell depletion reportedly leads to alterations in the T‐cell compartment with predominant survival of memory phenotype CD4 T cells. Here, we asked whether the prevalence of memory T cells ...postdepletion results from their inherent resistance to depletion and/or to the homeostatic expansion of naive T cells and their phenotypic conversion to memory, which is known to occur in lymphopenic conditions. Using a ‘mosaic memory’ mouse model with trackable populations of alloreactive memory T cells, we found that treatment with murine antithymocyte globulin (mATG) or antilymphocyte serum (ALS) effectively depleted alloreactive memory CD4 T cells, followed by rapid homeostatic proliferation of endogenous CD4 T cells peaking at 4 days postdepletion, with no homeostatic advantage to the antigen‐specific memory population. Interestingly, naive (CD44lo) CD4 T cells exhibited the greatest increase in homeostatic proliferation following mATG treatment, divided more extensively compared to memory (CD44hi) CD4 T cells and converted to a memory phenotype. Our results provide novel evidence that memory CD4 T cells are susceptible to lymphodepletion and that the postdepletional T‐cell compartment is repopulated to a significant extent by homeostatically expanded naive T cells in a mouse model, with important important implications for immune alterations triggered by induction therapy.
In a mouse model thymoglobulin treatment results in depletion of naive as well as alloantigen‐specific memory T cells and the post‐depletional T cell compartment is repopulated to a significant extent by homeostatic expansion of naive T cells which convert to memory phenotypes.
Exposure of rhesus macaque fetuses for 24 h or neonates for 9 h to ketamine anesthesia causes neuroapoptosis in the developing brain. The current study clarifies the minimum exposure required for and ...the extent and spatial distribution of ketamine-induced neuroapoptosis in rhesus fetuses and neonates.
Ketamine was administered by IV infusion for 5 h to postnatal day 6 rhesus neonates or to pregnant rhesus females at 120 days' gestation (full term = 165 days). Three hours later, fetuses were delivered by cesarean section, and the fetal and neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by activated caspase-3 staining.
Both the fetal (n = 3) and neonatal (n = 4) ketamine-exposed brains had a significant increase in apoptotic profiles compared with drug-naive controls (fetal n = 4; neonatal n = 5). Loss of neurons attributable to ketamine exposure was 2.2 times greater in fetuses than in neonates. The pattern of neurodegeneration in fetuses was different from that in neonates, and all subjects exposed at either age had a pattern characteristic for that age.
The developing rhesus macaque brain is sensitive to the apoptogenic action of ketamine at both a fetal and neonatal age, and exposure duration of 5 h is sufficient to induce a significant neuroapoptosis response at either age. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains.
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