Interferon-γ couples CD8+ T cell avidity and differentiation during infection.

Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8+ T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with memory features. Overall, we propose that IFN-γ and virtual memory T cells fulfil a critical immunoregulatory role by enabling the coordination of T cell avidity and fate.

T cell phenotypes in COVID-19 - a living review.

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients' long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation.

Comparison of thermal and chemical enhanced recovery of DNAPL in saturated porous media: 2D tank pumping experiments and two-phase flow modelling.

Pumping experiments were performed in a 2D tank in order to estimate the recovery yield of pure heavy chlorinated organic compounds (DNAPL; dense non-aqueous phase liquids) by varying different parameters: permeability of the saturated zone, pumping flow rates, addition of surfactant and heating. Surfactant was added to decrease capillary forces involved in the entrapment of DNAPL in porous media while temperature was increased to reduce DNAPL viscosity (and hence increase its mobility). Chemical enhancement was performed with the addition of Sodium Dodecyl Benzene Sulfonate (SDBS) (at its Critical Micelle Concentration, to avoid DNAPL dissolution) and thermal enhancement was performed at 50 °C (to avoid DNAPL volatilization). The experiments were monitored with photography allowing, on the basis of image interpretation, to convert optical densities (OD) into water saturations (Sw). Image interpretations were compared with modelling results. The two-phase flow modelling was performed with the pressure-pressure formulation using capillary pressure and relative permeability functions based on the van Genuchten-Mualem equations. Measured volumes of DNAPL recovered as well as the displacement of the DNAPL-water interface (radius and height of the cone of depression) are consistent with the modelling results. Furthermore, chemical enhancement results in a significant increase in the recovery rates of DNAPL. The observed improvement in the recovery of DNAPL with chemical enhancement is due to the fact that: (i) the residual saturation inside the cone of depression is lower and (ii) the cone of depression radius and height increase. Thermal enhancement had no beneficial effect on DNAPL recovery rate or yield. This study shows that it is possible to accurately determine water and DNAPL saturations by image interpretation during pumping tests in a 2D tank in the laboratory. For field-scale applications, the two-phase flow model allows to determine remediation yields as well as the volumes of the cone of depression according to the different operating conditions.

Modes of Communication between T Cells and Relevance for Immune Responses.

T cells are essential mediators of the adaptive immune system, which constantly patrol the body in search for invading pathogens. During an infection, T cells that recognise the pathogen are recruited, expand and differentiate into subtypes tailored to the infection. In addition, they differentiate into subsets required for short and long-term control of the pathogen, i.e., effector or memory. T cells have a remarkable degree of plasticity and heterogeneity in their response, however, their overall response to a given infection is consistent and robust. Much research has focused on how individual T cells are activated and programmed. However, in order to achieve a critical level of population-wide reproducibility and robustness, neighbouring cells and surrounding tissues have to provide or amplify relevant signals to tune the overall response accordingly. The characteristics of the immune response-stochastic on the individual cell level, robust on the global level-necessitate coordinated responses on a system-wide level, which facilitates the control of pathogens, while maintaining self-tolerance. This global coordination can only be achieved by constant cellular communication between responding cells, and faults in this intercellular crosstalk can potentially lead to immunopathology or autoimmunity. In this review, we will discuss how T cells mount a global, collective response, by describing the modes of T cell-T cell (T-T) communication they use and highlighting their physiological relevance in programming and controlling the T cell response.

Paracrine costimulation of IFN-γ signaling by integrins modulates CD8 T cell differentiation.

The cytokine IFN-γ is a critical regulator of immune system development and function. Almost all leukocytes express the receptor for IFN-γ, yet each cell type elicits a different response to this cytokine. Cell type-specific effects of IFN-γ make it difficult to predict the outcomes of the systemic IFN-γ blockade and limit its clinical application, despite many years of research. To better understand the cell-cell interactions and cofactors that specify IFN-γ functions, we focused on the function of IFN-γ on CD8 T cell differentiation. We demonstrated that during bacterial infection, IFN-γ is a dominant paracrine trigger that skews CD8 T cell differentiation toward memory. This skewing is preferentially driven by contact-dependent T cell-T cell (T-T) interactions and the localized IFN-γ secretion among activated CD8 T cells in a unique splenic microenvironment, and is less sensitive to concurrent IFN-γ production by other immune cell populations such as natural killer (NK) cells. Modulation of CD8 T cell differentiation by IFN-γ relies on a nonconventional IFN-γ outcome that occurs specifically within 24 hours following infection. This is driven by IFN-γ costimulation by integrins at T-T synapses, and leads to synergistic phosphorylation of the proximal STAT1 molecule and accelerated IL-2 receptor down-regulation. This study provides evidence of the importance of context-dependent cytokine signaling and gives another example of how cell clusters and the microenvironment drive unique biology.

Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico.

Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals who develop high titers of anti-ZIKV antibodies, we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with pre-existing reactivity to DENV1 in humans.

[Severe poisoning by plants used for traditional medicine in Mayotte]. / Intoxications graves lors de traitements traditionnels par les plantes à Mayotte.

The authors describe three cases of severe accidental poisoning by plants used as part of a traditional treatment in Mayotte. The established, or suspected, toxicity of Thevetia peruviana (Yellow oleander), Cinchona pubescens (Red quinine-tree), Melia azaderach (Persian lilac, also called china berry) and Azadirachta indica (Neem), is discussed. The clinical presentation is cardiac (atrioventricular block) and well known for Thevetia and Cinchona intoxications. Neurological signs and multi-organ failure are found for Azadirachta and Melia. The identification of the plants is never easy, nor is the evidence of their accountability. In the three cases reported, no other cause than the traditional treatment has been found to explain the clinical presentation. The outcome was favorable in all cases. The authors emphasize the difficulties to investigate these accidents, the poor medical knowledge of these practices in tropical areas, and in Mayotte particularly. The need for cooperation with local botanists, familiar with traditional medicine, is also underlined.

[Pulmonary oedema in scuba-diving: frequency and seriousness about a series of 19 cases]. / L'oedème pulmonaire en plongée sous-marine autonome: fréquence et gravité à propos d'une série de 19 cas.

OBJECTIVES: Pulmonary oedema in self-contained underwater breathing apparatus diving is an accident whose risk factors, conditions of occurrence and incidence are not well-known. The aim of this study was to evaluate the frequency, the risk factors and the evolution of this accident. STUDY DESIGN: Retrospective case study and prospective frequency study. PATIENTS AND METHODS: Study covering the Brittany region and performed in two steps with distinct objectives: a review of cases diagnosed between 2002 and 2007, and a one-year study of cases reported by emergency physicians. Diagnosis was based on the history, a respiratory distress, auscultation and radiologic features. RESULTS: Nineteen cases were reported, of which one was recurrent. The mean age of patients was 49 years. Divers without heart disease were involved, as well as divers with hypertension (eight cases) or valve abnormalities (three cases). Stress and/or physical exertion were involved. Dyspnoea, cough and haemoptysis were the most common symptoms; in addition, two cases of cardiac arrest and three of loss of consciousness were observed. Chest radiography was unsensitive (normal in four cases), contrasting with abnormal thoracic CT scan in all cases. Symptoms resolved rapidly with oxygen, except for two divers who died. We identified five cases over one year, one of which lethal. CONCLUSION: This accident is not a rare event and may have serious consequences. Oldest divers submitted to stress and/or effort are at higher risk.

[Evaluation of the renal function in cardiac surgery with CPB: role of the cystatin C and the calculated creatinine clearance]. / Evaluation de la fonction rénale périopératoire en chirurgie cardiaque: rôle de la cystatine C et de clairance de la créatinine calculée.

OBJECTIVES: The evaluation of the renal function in cardiac surgery is difficult. The gold standard remains the creatinine clearance in clinical practice. Cystatin C was recently proposed in order to evaluate the renal function. The aim of our study was to evaluate the cystatin C in cardiac surgery with CPB. PATIENTS AND METHODS: After informed consent and ethical committee agreement, 60 patients operated in cardiac surgery with CPB were prospectively included. Cystatin C,measured and calculated (Cockcroft and MDRD methods) creatinine were compared with the Student t-test and with the Bland and Altman method. p<0,05 was considered as a significant threshold. RESULTS: The reproducibility of the calculated creatinine clearance was better when the urinary collecting time was below 400 minutes. The estimation of the creatinine clearance by the Cockcroft and MDRD methods is better when the clearance is low. A significant correlation between the creatinine clearance and the cystatin C does exist, but the correlation coefficient was low. In case of acute renal dysfunction, the increase of the creatinine occurred earlier than the increase of the cystatin C. CONCLUSION: In cardiac surgery with CPB, the evaluation of the renal function was not improved by the cystatin C.

[Arterial gas embolism originating from the lung in anaesthesia and intensive care]. / Embolies gazeuses artérielles d'origine pulmonaire en anesthésie-réanimation.

We report seven cases of arterial gas embolism originating from the lung that occurred in anaesthesia and intensive care unit in the very hospital where our regional hyperbaric oxygen facility is. They complicated lung surgery or trauma and/or followed a support by positive-pressure ventilation. Diagnosis was most often delayed, because of some scepticism of the physicians confronted with a variety of clinical features. The prognosis was bad with four deaths, despite treatment with hyperbaric oxygen in three cases.

[A standardised histopathological worksheet for the histopathologic examination of primary cutaneous melanomas. Experiences at the Gustave-Roussy Institute]. / Fiche standardisée pour les résultats de l'examen histopathologique des mélanomes cutanés primitifs. Expérience de l'Institut Gustave-Roussy.

A standardised worksheet for the histopathology report of primary cutaneous melanoma used at the Gustave-Roussy Institute is described. Each item is discussed.

[Dominant cystoid macular dystrophy (author's transl)]. / Dégénérescence maculaire cystoïde dominante (D.M.C.D.)

Dominant cystoid macular dystrophy (D.C.M.D.) is characterized by a macular dystrophy but at the same time by a pigmentary dystrophy of the retinal periphery. Ultimately D.C.M.D. resembles an atypical pigmentary dystrophy, in some cases that of a pericentral retinitis pigmentosa. In an early stage the results of the EOG and darkadaptation curve reflect the process at the level of the peripheral retina, while only in a late stage we may expect some diffuse ERG pathology. D.C.M.D. might be classified as a tapetoretinal dystrophy and in particular as a form of retinitis pigmentosa with an atypical visual disturbance and an atypical fundus appearance (Leber, 1871). In doing so attention is paid to the fact that D.C.M.D. is more than a macular dystrophy. The denomination of the disease as D.C.M.D. reflects the most important features at a relatively young age.

Biochemical aspects of the visual process. XXVII. Stereospecificity of ocular retinol dehydrogenases and the visual cycle.

A comparative study is made of the stereospecificity of two particulate retinol dehydrogenases from bovine eyes and of horse liver alcohol dehydrogenase. The particulate retinol dehydrogenase of outer segments reacts with the all-trans isomers of retinaldehyde and retinol but not with the 11-cis compounds. In contrast, a particulate retinol dehydrogenase present in pigment epithelium reacts preferentially with the 11-cis compounds. Horse liver alcohol dehydrogenase (EC 1.1.1.1.) can convert both isomers, but the all-trans isomers are clearly preferred. Differences with regard to cofactor preference and stability are also noted. The outer segment enzyme clearly functions in the rhodopsin cycle. It is unlikely that the 11-cis retinol dehydrogenase from pigment epithelium is directly involved in providing 11-cis retinaldehyde from rhodopsin regeneration, but it may serve to make available 11-cis retinaldehyde from rhodopdsin, digested in phagocytized rod sacs, for the synthesis of visual pigment by the visual cells.