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

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

Unconventional Repertoire Profile Is Imprinted during Acute Chikungunya Infection for Natural Killer Cells Polarization toward Cytotoxicity

Chikungunya virus (CHIKV) is a worldwide emerging pathogen. In humans it causes a syndrome characterized by high fever, polyarthritis, and in some cases lethal encephalitis. Growing evidence indicates that the innate immune response plays a role in controlling CHIKV infection. We show here that CHIKV induces major but transient modifications in NK-cell phenotype and function soon after the onset of acute infection. We report a transient clonal expansion of NK cells that coexpress CD94/NKG2C and inhibitory receptors for HLA-C1 alleles and are correlated with the viral load. Functional tests reveal cytolytic capacity driven by NK cells in the absence of exogenous signals and severely impaired IFN-γ production. Collectively these data provide insight into the role of this unique subset of NK cells in controlling CHIKV infection by subset-specific expansion in response to acute infection, followed by a contraction phase after viral clearance

Diverse aging rates in ectothermic tetrapods provide insights for the evolution of aging and longevity

Comparative studies of mortality in the wild are necessary to understand the evolution of aging; yet, ectothermic tetrapods are underrepresented in this comparative landscape, despite their suitability for testing evolutionary hypotheses. We present a study of aging rates and longevity across wild tetrapod ectotherms, using data from 107 populations (77 species) of nonavian reptiles and amphibians. We test hypotheses of how thermoregulatory mode, environmental temperature, protective phenotypes, and pace of life history contribute to demographic aging. Controlling for phylogeny and body size, ectotherms display a higher diversity of aging rates compared with endotherms and include phylogenetically widespread evidence of negligible aging. Protective phenotypes and life-history strategies further explain macroevolutionary patterns of aging. Analyzing ectothermic tetrapods in a comparative context enhances our understanding of the evolution of aging.Animal science

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Cyanide Suicide After Deep Web Shopping: A Case Report

International audienceCyanide is a product that is known for its use in industrial or laboratory processes, as well as for intentional intoxication. The toxicity of cyanide is well described in humans with rapid inhibition of cellular aerobic metabolism after ingestion or inhalation, leading to severe clinical effects that are frequently lethal. We report the case of a young white man found dead in a hotel room after self-poisoning with cyanide ordered in the deep Web. This case shows a probable complex suicide kit use including cyanide, as a lethal tool, and dextromethorphan, as a sedative and anxiolytic substance. This case is an original example of the emerging deep Web shopping in illegal drug procurement

Outil d’aide à la décision pour les commissions pluridisciplinaires de pénibilité pour les accidents du travail

International audienceLa loi du 9 novembre 2010 relative à la réforme des retraites a introduit la notion de pénibilité professionnelle et la possibilité de compenser celle-ci, sous certaines conditions, par un départ anticipé à la retraite. Cette possibilité est de droit pour les personnes atteintes d’une maladie professionnelle responsable d’une incapacité permanente partielle d’au moins 10 %. Elle est étendue aux victimes d’accidents du travail responsables de lésions analogues à celles constatées en maladie professionnelle (listées réglementairement). Lorsque le taux d’incapacité est compris entre 10 et 20 %, l’avis de la commission pluridisciplinaire de pénibilité est sollicité. L’objet de notre travail a été de proposer un outil méthodologique d’aide décisionnelle à l’usage de ces commissions

Sécurité et efficacité de l’immunothérapie selon un schéma double dose dans le CBNPC avancé : étude rétrospective multicentrique IDEE

National audienceAu cours de la pandémie COVID-19, l’utilisation du pembrolizumab à 400 mg toutes les 6 semaines et Nivolumab 480 4 a été proposée pour limiter venues patients porteurs d’un CBNPC avancé. Cette proposition reposait uniquement sur des données pharmacocinétique pharmacodynamie compatible. L’étude IDEE objectif principal déterminer sécurité l’efficacité ce schéma thérapeutique en condition vie réelle. Nous avons réalisé une étude observationnelle, rétrospective, multicentrique dans centres hospitaliers bretons. Tous atteints avancé ayant reçu au moins dose adaptée entre le 1er mars 2020 2021 ont inclus l’étude. Le suivi effectué jusqu’en 2022. Les cliniques recueillies partir dossiers médicaux. Quatre-vingt-onze l’étude (38 nivolumab semaines, 53 semaines). L’âge médian l’inclusion était 68 ans. La plupart avaient un stade IV (n = 7