NK Cell Terminal Differentiation: Correlated Stepwise Decrease of NKG2A and Acquisition of KIRs

BACKGROUND: Terminal differentiation of NK cells is crucial in maintaining broad responsiveness to pathogens and discriminating normal cells from cells in distress. Although it is well established that KIRs, in conjunction with NKG2A, play a major role in the NK cell education that determines whether cells will end up competent or hyporesponsive, the events underlying the differentiation are still debated. METHODOLOGY/PRINCIPAL FINDINGS: A combination of complementary approaches to assess the kinetics of the appearance of each subset during development allowed us to obtain new insights into these terminal stages of differentiation, characterising their gene expression profiles at a pan-genomic level, their distinct surface receptor patterns and their prototypic effector functions. The present study supports the hypothesis that CD56dim cells derive from the CD56bright subset and suggests that NK cell responsiveness is determined by persistent inhibitory signals received during their education. We report here the inverse correlation of NKG2A expression with KIR expression and explore whether this correlation bestows functional competence on NK cells. We show that CD56dimNKG2A-KIR+ cells display the most differentiated phenotype associated to their unique ability to respond against HLA-E+ target cells. Importantly, after IL-12+IL-18 stimulation, reacquisition of NKG2A strongly correlates with IFN-gamma production in CD56dimNKG2A- NK cells. CONCLUSIONS/SIGNIFICANCE: Together, these findings call for the reclassification of mature human NK cells into distinct subsets and support a new model, in which the NK cell differentiation and functional fate are based on a stepwise decrease of NKG2A and acquisition of KIRs

Senescent cells evade immune clearance via HLA-E-mediated NK and CD8(+) T cell inhibition

Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8 + T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C

CD56negCD16+NK cells are activated mature NK cells with impaired effector function during HIV-1 infection

BACKGROUND: A subset of CD3(neg)CD56(neg)CD16(+) Natural Killer (NK) cells is highly expanded during chronic HIV-1 infection. The role of this subset in HIV-1 pathogenesis remains unclear. The lack of NK cell lineage-specific markers has complicated the study of minor NK cell subpopulations. RESULTS: Using CD7 as an additional NK cell marker, we found that CD3(neg)CD56(neg)CD16(+) cells are a heterogeneous population comprised of CD7(+) NK cells and CD7(neg) non-classical myeloid cells. CD7(+)CD56(neg)CD16(+) NK cells are significantly expanded in HIV-1 infection. CD7(+)CD56(neg)CD16(+) NK cells are mature and express KIRs, the C-type lectin-like receptors NKG2A and NKG2C, and natural cytotoxicity receptors similar to CD7(+)CD56(+)CD16(+) NK cells. CD7(+)CD56(neg) NK cells in healthy donors produced minimal IFNγ following K562 target cell or IL-12 plus IL-18 stimulation; however, they degranulated in response to K562 stimulation similar to CD7(+)CD56(+) NK cells. HIV-1 infection resulted in reduced IFNγ secretion following K562 or cytokine stimulation by both NK cell subsets compared to healthy donors. Decreased granzyme B and perforin expression and increased expression of CD107a in the absence of stimulation, particularly in HIV-1-infected subjects, suggest that CD7(+)CD56(neg)CD16(+) NK cells may have recently engaged target cells. Furthermore, CD7(+)CD56(neg)CD16(+) NK cells have significantly increased expression of CD95, a marker of NK cell activation. CONCLUSIONS: Taken together, CD7(+)CD56(neg)CD16(+) NK cells are activated, mature NK cells that may have recently engaged target cells

A cream containing the sap of oat plantlets and mandarin extract soothes the symptoms of rosacea and improves the quality of life of patients

Rosacea is a chronic inflammatory disease of the facial skin that affects all skin types and occurs mostly in adults. The main clinical sign of rosacea is a characteristic and persistent form of centro-facial erythema that is prone to exacerbation and can impair quality of life (QoL). The current therapeutic approach for rosacea is to combine various treatments, use appropriate skincare products and avoid flare-up triggers

Formation and deformation of pyrite and implications for gold mineralization in the El Callao district, Venezuela

The El Callao mining district is the most important gold-producing region in Venezuela. It is hosted in the Paleoproterozoic Guasipati-El Callao greenstone belt, which forms part of the Guayana craton, the Venezuelan extension of the Guiana Shield of South America. It consists of volcanic and volcanosedimentary sequences that were affected by several deformation events, particularly localized shear zones. The Colombia mine, the largest active mine in the district, produces 4 tonnes (t) (128,600 oz) of gold annually with reserves estimated at 740 t (24 Moz) and grades of up to 60 g/t. Gold mineralization is concentrated within a vein network in the Colombia corridor, a shear fracture-hosted mesh of interconnected quartz-ankerite-albite veins enclosing fragments of altered metabasaltic host rocks. Gold occurs mostly in the metabasaltic fragments and is spatially associated with pyrite, in which it occurs as invisible gold, micron-sized native gold inclusions, and filling fractures. Based on optical and scanning electron microscopy-backscattered electron observations, two types of pyrite are recognized: a simple-zoned pyrite and a less common oscillatory-zoned pyrite. Both types consist of a mineral inclusion-rich core and a clearer rim; however, in oscillatory-zoned pyrite, the latter is composed of complex rhythmic overgrowths of alternating As-rich and As-poor bands. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) analysis and elemental mapping reveal the presence of invisible gold in all generations of pyrite. The highest concentrations (5-23 ppm Au) are found in oscillatory-zoned pyrite rims, which correlate with the highest As concentrations (16,000-23,000 ppm). In As-poor bands, Au (up to 1.5 ppm) and As (300-6,000 ppm) concentrations decrease by about an order of magnitude. Copper, Bi, Te, Sb, Pb, and Ag always occur with invisible gold, particularly in pyrite cores, suggesting that at least part of the gold occurs in sulfosalt nanoparticles of these metals and metalloids. Visible native gold grains occur as small inclusions throughout core and rim of both pyrite types, as well as in fractures within it. In both occurrences, chalcopyrite, sphalerite, tellurobismuthite, ankerite, albite, and chlorite accompany native gold, and gold fineness ranges between 900 and 930. At an early stage of vein mesh formation, pyrite formed in the metabasaltic fragments at the expense of ankerite, which, in turn, resulted from alteration of Fe-Ti oxides. Gold, together with other chalcoplaile elements, was incorporated within the structure of pyrite, most likely by destabilization of metal sulfide complexes during ankerite replacement. Subsequent cyclic reactivations of the shear zone caused development of pressure shadows around pyrite, generating local and repeated decreases in pressure, which triggered local boiling of the hydrothermal fluid, as evidenced by the presence of primary fluid inclusions containing immiscible liquid-rich and vapor-rich aqueous-carbonic fluids. This process was responsible for a number of physical-chemical changes in the liquid, all of which contributed to the formation of the As- and Au-rich overgrowths in pyrite: (1) removal of H2O into the vapor phase, inducing saturation of dissolved metals in the remaining liquid; (2) an increase in pH due to partition of H2S and CO2 into the vapor, thus decreasing the solubility of sulfide minerals; and (3) an adiabatic decrease in temperature, lowering the solubility of As and Au in the liquid. Waning of this process restored precipitation of As-poor pyrite, until the onset of a new cycle. Because pressure drops are more significant adjacent to open spaces, oscillatory-zoned pyrite probably crystallized near newly formed veins whereas simple-zoned pyrite formed away from them. Previously formed pyrite underwent fracturing during reactivation of the deformation, especially through the brittle deformation events that postdated shearing, resulting in local pulverization of pyrite. This newly created porosity facilitated fluid circulation and r

The CarboEurope Regional Experiment Strategy

Models and observational strategies of carbon exchange need to take into account synoptic and mesoscale transport for correct interpretation of the relation between surface fluxes and atmospheric ceoncentration gradients