Group 3 innate lymphoid cells (ILC3) have a prominent role in the maintenance of intestine mucosa homeostasis. The hypoxia-inducible factor (HIF) is an important modulator of immune cell activation ...and a key mechanism for cellular adaptation to oxygen deprivation. However, its role on ILC3 is not well known. In this study, we investigated how a hypoxic environment modulates ILC3 response and the subsequent participation of HIF-1 signaling in this process. We found increased proliferation and activation of intestinal ILC3 at low oxygen levels, a response that was phenocopied when HIF-1α was chemically stabilized and was reversed when HIF-1 was blocked. The increased activation of ILC3 relied on a HIF-1α-dependent transcriptional program, but not on mTOR-signaling or a switch to glycolysis. HIF-1α deficiency in RORyt compartment resulted in impaired IL-17 and IL-22 production by ILC3 in vivo, which reflected in a lower expression of their target genes in the intestinal epithelium and an increased susceptibility to Clostridiodes difficile infection. Taken together, our results show that HIF-1α activation in intestinal ILC3 is relevant for their functions in steady state and infectious conditions.
Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led ...to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1
/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC precursor and the pre-NK cell progenitor. We further demonstrate that the pan-JAK inhibitor tofacitinib and the specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis. Both tofacitinib and PF-06651600 are currently in clinical trials for several other immune-mediated conditions. Our data suggest that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy.
Survival rates of lung cancer remains poor and the impact of comorbidities on the prognosis is discussed. The objective of this study was to assess if the Charlson Comorbidity Index (CCI) was ...associated with 8-year survival rates by histological type.
A cohort study was conducted using randomly selected cases from 10 French cancer registries. Net survival rates were computed using the Pohar-Perme estimator of the net cumulative rate. Three Cox models were independently built for adenocarcinomas, squamous cell and small cell cancers to estimate prognostic factors including CCI grade.
A total of 646 adenocarcinomas, 524 squamous cell and 233 small cell cancers were included in the analysis. The net 8-year survival rate ranged from 12.6% (95% CI: 9.8-15.4%) for adenocarcinomas and 13.4% (95% CI: 10.1-16.7%) for squamous cell carcinomas, to 3.7% (95% CI: 1.1-6.3%) for small cell cancers. Observed and net survival rates decreased for CCI grades ≥3 for all histological group considered. After adjustment for sex, age group, stage and diagnostic mode, CCI grades 1 (HR = 1.6 95% CI: 1.1-2.3), 2 (HR = 1.7 95% CI: 1.1-2.7) and ≥ 3 (HR = 2.7 95% CI: 1.7-4.4) were associated with lower survival rates only for small cell cancers.
After adjustment for age, sex, stage and diagnostic mode, the presence of comorbidity based on CCI grades 1-2 and ≥ 3 was associated with lower survival rates for small cell cancers whereas no differences were observed for adenocarcinomas and squamous cell cancers.
•Short term projections showed the high prevalence of persons alive with previous cancer diagnosis in a high-income country.•Trends in prevalence were influenced by incidence, survival and demography ...among ≥65y and by incidence and survival among <65y.•Time variation of prevalence among men was influenced by the recent incidence decrease of prostate cancer.
This study analyzes time trends in cancer prevalence in France and provides short-term projections up to the year 2017. The 15-year prevalence for 24 cancers was estimated from the French cancer registries network (FRANCIM) incidence and survival data.
We estimated prevalence using the P = I × S relationship, with flexible modeling of incidence and survival. Based on observations of the incidence and survival up to 2010, different scenarios for evolution up to 2017 were studied, combining stable and dynamic incidence and survival. The determinants of variations in prevalence (incidence, survival and demography) were quantified.
At the end of 2017, an estimated 1,396,000 men and 1,359,000 women having had cancer in the previous 15 years were alive, respectively 5.4% and 4.8% of the population. Twelve percent had been diagnosed in the preceding year and 23% between 10 and 15 years. Between 2010 and 2017, changes in incidence and survival depended on the cancer site. The effect of the demographic change was null for those under age 65, whereas above age 65, the contribution of this factor was 20% in men and 17% in women at 15 years. The different projection scenarios led to very different estimates for some cancers for which incidence strongly varied in the last decades.
Prevalent cases are numerous in a country such as France, where incidence and survival are high. Due to the sensitivity of prevalence to changes in incidence and survival, we recommend that the results of projections are presented under different scenarios. We propose a robust and flexible prevalence estimate.
Immunoglobulin-like transcript 3 (ILT3) and ILT4 belong to a family of inhibitory receptors expressed by human monocytes and dendritic cells. We show here that CD8+CD28(-) alloantigen-specific T ...suppressor (TS) cells induce the up-regulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering these antigen-presenting cells (APCs) tolerogenic. Tolerogenic APCs show reduced expression of costimulatory molecules and induce antigen-specific unresponsiveness in CD4+ T helper cells. Studies of human heart transplant recipients showed that rejection-free patients have circulating TS cells, which induce the up-regulation of ILT3 and ILT4 in donor APCs. These findings demonstrate an important mechanism of immune regulation.
Gene targeting of the adaptor molecule DAP12 in mice caused abnormal distribution and impaired antigen presentation capacity of dendritic cells (DCs). However, the DAP12-associated receptors ...expressed on DCs and their functions have not been identified yet. Here we show that the triggering receptor expressed on myeloid cells-2 (TREM-2) is a cell surface receptor on human monocyte-derived DCs, which is associated with DAP12. TREM-2/DAP12 promotes upregulation of CC chemokine receptor 7, partial DC maturation, and DC survival through activation of protein tyrosine kinases and extracellular signal-regulated kinase. In contrast to Toll-like receptor-mediated signaling, TREM2/DAP12 stimulation is independent of nuclear factor-kappaB and p38 stress-activated protein kinase. This novel DC activation pathway may regulate DC homeostasis and amplify DC responses to pathogens, explaining the phenotype observed in DAP12-deficient mice.
Highlights on the recent research activity, carried out by the Italian Community involved in the "Nuclear matter and nuclear dynamics" field, will be presented. In particular, we discuss new results ...on the Equation of State (EOS) of asymmetric nuclear matter, from microscopic many-body approaches on one side and from the study of sensitive observables in dissipative nuclear reactions on the other. Considering a wide range of beam energies, it is possible to explore the behavior of the EOS symmetry term in several conditions of density and temperature. New results concerning the structure and the life of neutron stars, that are affected by the high density behavior of asymmetric nuclear matter, will also be reported.
The production/absorption rate of particles in compressed and heated asymmetric matter is studied using a Relativistic Mean Field (RMF) transport model with an isospin-dependent collision term. Just ...from energy conservation in the elementary production/absorption processes we expect to see a strong dependence of the yields on the basic Lorentz structure of the isovector effective interaction, due to isospin effects on the scalar and vector self-energies of the hadrons. This will be particularly evident for the ratio of the rates of particles produced with different charges: results are shown for
π
+
/
π
−
,
K
+
/
K
0
yields.
In order to simplify the analysis we perform RMF cascade simulations in a box with periodic boundary conditions. In this way we can better pin down all such fine relativistic effects in particle production, that could likely show up even in realistic heavy ion collisions. In fact, the box properties are tuned in order to reproduce the heated dense matter formed during a nucleus–nucleus collision in the few
A GeV beam energy region.
In particular,
K
+
,
0
production is expected to be directly related to the high density behaviour of the symmetry energy, since kaons are produced very early during the high density stage of the collision and their mean free path is rather large. We show that the
K
+
/
K
0
ratio reflects important isospin contributions on the production rates just because of the large sensitivity around the threshold. The results are very promising for the possibility of a direct link between particle production data in exotic Heavy Ion Collisions (HIC) and the isospin-dependent part of the Equation of State (EoS) at high baryon densities.
Blood, lymphoid tissues, and placenta contain diverse subpopulations of natural killer (NK) cells that possess distinct immune functions. Recent studies have shown that human and mouse gut-associated ...lymphoid tissues harbor a unique NK cell subset that specializes in production of interleukin (IL)-22. This cytokine plays a role in host defense of mucosal barriers, although dysregulated secretion may cause autoimmune disease. In parallel, human fetal lymphoid tissue inducer (LTi) cells and mouse adult LTi-like cells in secondary lymphoid tissues were found to release IL-22, as well as IL-17, a proinflammatory cytokine that mediates host defense against extracellular pathogens. Here, we compare these recently identified immune cells, reviewing what is known about their anatomical location, differentiation requirements, function, and potential involvement in host defense and autoimmunity. Finally, we discuss the challenges faced in furthering our understanding of the developmental relationships and role of NK and LTi-like cells in mucosal immune responses.
TREMs in the immune system and beyond Colonna, Marco
Nature reviews. Immunology,
200306, 2003-Jun, 2003-06-01, 20030601, Letnik:
3, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Triggering receptors expressed by myeloid cells (TREMs) belong to a rapidly expanding family of receptors that include activating and inhibitory isoforms encoded by a gene cluster linked to the MHC. ...TREM1 and TREM2 activate myeloid cells by signalling through the adaptor protein DAP12. TREM1 triggers phagocyte secretion of pro-inflammatory chemokines and cytokines, amplifying the inflammation that is induced by bacteria and fungi. TREM2 activates monocyte-derived dendritic cells and regulates osteoclast development. Remarkably, TREM2 deficiency leads to a severe disease that is characterized by bone cysts and demyelination of the central nervous system, which results in dementia, implying that the function of TREM2 extends beyond the immune system.
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