Natural Killer (NK) cells hold the potential to shift cell therapy from a complex autologous option to a universal off-the-shelf one. Although NK cells have demonstrated efficacy and safety in the ...treatment of leukemia, the limited efficacy of NK cell-based immunotherapies against solid tumors still represents a major hurdle. In the immunosuppressive tumor microenvironment (TME), inhibitory interactions between cancer and immune cells impair antitumoral immunity.
gene encodes the NK cell inhibitory receptor NKG2A, which is a potent NK cell immune checkpoint. NKG2A specifically binds HLA-E, a non-classical HLA class I molecule frequently overexpressed in tumors, leading to the transmission of inhibitory signals that strongly impair NK cell function.
To restore NK cell cytotoxicity against HLA-E
tumors, we have targeted the NKG2A/HLA-E immune checkpoint by using a CRISPR-mediated
gene editing.
knockout resulted in a reduction of 81% of NKG2A
cell frequency in
expanded human NK cells post-cell sorting.
, the overexpression of HLA-E by tumor cells significantly inhibited wild-type (WT) NK cell cytotoxicity with
-values ranging from 0.0071 to 0.0473 depending on tumor cell lines. In contrast,
NK cells exhibited significantly higher cytotoxicity when compared to WT NK cells against four different HLA-E
solid tumor cell lines, with
-values ranging from<0.0001 to 0.0154. Interestingly, a proportion of 43.5% to 60.2% of NKG2A
NK cells within the edited NK cell population was sufficient to reverse at its maximum the HLA-E-mediated inhibition of NK cell cytotoxicity. The expression of the activating receptor NKG2C was increased in
NK cells and contributed to the improved NK cell cytotoxicity against HLA-E
tumors.
, the adoptive transfer of human
NK cells significantly delayed tumor progression and increased survival in a xenogeneic mouse model of HLA-E
metastatic breast cancer, as compared to WT NK cells (
= 0.0015).
Our results demonstrate that
knockout is an effective strategy to improve NK cell antitumor activity against HLA-E
tumors and could be applied in the development of NK cell therapy for solid tumors.
In patients with HIV/AIDS receiving antiretroviral therapy (ART), HIV-1 persistence in brain tissue is a vital and unanswered question. HIV-1 infects and replicates in resident microglia and ...trafficking macrophages within the brain although the impact of individual ART drugs on viral infection within these brain myeloid cells is unknown. Herein, the effects of contemporary ART drugs were investigated using in vitro and in vivo models of HIV-1 brain infection.
The EC
values for specific ART drugs in HIV-infected human microglia were significantly higher compared to bone marrow-derived macrophages and peripheral blood mononuclear cells. Intracellular ART drug concentrations in microglia were significantly lower than in human lymphocytes. In vivo brain concentrations of ART drugs in mice were 10 to 100-fold less in brain tissues compared with plasma and liver levels. In brain tissues from untreated HIV-infected BLT mice, HIV-encoded RNA, DNA and p24 were present in human leukocytes while ART eradicated viral RNA and DNA in both brain and plasma. Interruption of ART resulted in detectable viral RNA and DNA and increased human CD68 expression in brains of HIV-infected BLT mice. In aviremic HIV/AIDS patients receiving effective ART, brain tissues that were collected within hours of last ART dosing showed HIV-encoded RNA and DNA with associated neuroinflammatory responses.
ART drugs show variable concentrations and efficacies in brain myeloid cells and tissues in drug-specific manner. Despite low drug concentrations in brain, experimental ART suppressed HIV-1 infection in brain although HIV/AIDS patients receiving effective ART had detectable HIV-1 in brain. These findings suggest that viral suppression in brain is feasible but new approaches to enhancing ART efficacy and concentrations in brain are required for sustained HIV-1 eradication from brain.
Macrophages populate the embryo early in gestation, but their role in development is not well defined. In particular, specification and function of macrophages in intestinal development remain little ...explored. To study this event in the human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrate into the organoid, proliferate, and occupy the emerging microanatomical niches of epithelial crypts and ganglia. They also acquire a transcriptomic profile similar to that of fetal intestinal macrophages and display tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to the regulation of metabolism and growth of the developing intestine.
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•PSC-derived multi-cell-type intestinal organoid populated with macrophages•Recapitulate aspects of microanatomical localization and transcriptomic changes•Macrophages in the organoid downregulate glycolysis of mesenchymal cells•Macrophages in the organoid limit tissue growth without affecting the architecture
Song et al. grew pluripotent stem cell-derived miniature intestinal tissue populated with macrophages. Macrophages within the tissue recapitulate aspects of microanatomical localization and transcriptomic changes observable in developing intestinal macrophages. They downregulate glycolysis of mesenchymal cells within the tissue. They also limit its growth without affecting the architecture.
Dengue virus (DENV), chikungunya virus (CHIKV), and Zika virus (ZIKV) infections are rapidly expanding across countries and are being diagnosed in returned travellers who represent epidemiological ...sentinels. The French Territories of America (FTA) such as Guadeloupe and Martinique see high levels of tourism and have experienced three consecutive outbreaks by these viruses in the last decade.
This study was performed to evaluate how ill returned travellers could have represented epidemiological sentinels for these three expanding arboviral diseases over eight consecutive years. The degree of correlation between the cases of ill returned travellers arriving at a French tertiary hospital in Paris and the three outbreaks that occurred in the FTA during the study period was estimated.
All consecutive ill returned travellers diagnosed at the hospital in Paris with imported DENV, CHIKV, or ZIKV infections from January 2009 to December 2016 were included. Epidemiological and clinical variables were evaluated. Data concerning the incidence of arboviruses in the FTA, as well as the temporal relationship between the occurrence of imported cases and outbreaks in the FTA, were analyzed.
Overall, 320 cases of arboviral infection were reported: 216 DENV, 68 CHIKV, and 36 ZIKV. Most of the patients presented with fever and exanthema. One hundred and fifteen patients were exposed in Guadeloupe or Martinique, which were the at-risk destinations in 25% of patients with DENV, 59% of patients with CHIKV, and 58% of patients with ZIKV. The occurrence of cases diagnosed in returning travellers followed the same time pattern as the outbreaks in these areas.
A temporal correlation was found between newly diagnosed imported cases of arboviruses and the three corresponding outbreaks that occurred in Martinique and Guadeloupe during 8 consecutive years. Thus, ill returned travellers act as epidemiological sentinels from the beginning up to the end of outbreaks occurring in touristic locations.
Introduction
While
18
F-FDG PET/CT pediatrics applications have increased in number and indications, few studies have addressed normal maximum standardized uptake values (SUV
max
) of referral organs ...in children. The purpose of this study is to assess these in a cohort of pediatric patients.
Material and methods
285
18
F-FDG PET/CT scans in 229 patients were reviewed. SUV
max
were assessed for mediastinal blood pool (MBP), thymus (T), liver (L), spleen (S), bone marrow (BM) and Waldeyer’s Ring (Wald). L/MBP and S/L ratios were calculated. Same day complete blood counts (CBC) were available for 132 studies and compared to BM and S. Means, standard deviations and correlation coefficients with age, weight and body surface area (BSA) were calculated.
Results
Weak correlation with age, weight or BSA was found for Wald. Strong correlations with weight/BSA more than with age were demonstrated for MBP, L and BM and moderate for S and T. After initial decrease between age 0 and 2, thymic activity peaked at age 11 years then involuted. No correlation was found between CBC ad BM or S. In 28 studies, L was less or equal to MBP. In 74 S was superior to L.
Conclusions
Referral organs
18
F-FDG uptake varies in children more in relation with weight and BSA than with age for key referral organs, such as L, S and MBP. In a significant number of studies, L activity may impede evaluation of treatment response in comparison with MBP or inflammation/infection evaluation in comparison with S.
Abstract
Background
Interleukin-27 (IL-27) can trigger both pro- and anti-inflammatory responses. This cytokine is elevated in the central nervous system (CNS) of multiple sclerosis (MS) patients, ...but how it influences neuroinflammatory processes remains unclear. As astrocytes express the receptor for IL-27, we sought to determine how these glial cells respond to this cytokine and whether such exposure alters their interactions with infiltrating activated T lymphocytes. To determine whether inflammation shapes the impact of IL-27, we compared the effects of this cytokine in non-inflamed and inflamed conditions induced by an IL-1β exposure.
Main body
Transcriptomic analysis of IL-27-exposed human astrocytes showed an upregulation of multiple immune genes. Human astrocytes increased the secretion of chemokines (CXCL9, CXCL10, and CXCL11) and the surface expression of proteins (PD-L1, HLA-E, and ICAM-1) following IL-27 exposure. To assess whether exposure of astrocytes to IL-27 influences the profile of activated T lymphocytes infiltrating the CNS, we used an astrocyte/T lymphocyte co-culture model. Activated human CD4
+
or CD8
+
T lymphocytes were co-cultured with astrocytes that have been either untreated or pre-exposed to IL‑27 or IL-1β. After 24 h, we analyzed T lymphocytes by flow cytometry for transcription factors and immune molecules. The contact with IL-27-exposed astrocytes increased the percentages of T-bet, Eomes, CD95, IL-18Rα, ICAM-1, and PD-L1 expressing CD4
+
and CD8
+
T lymphocytes and reduced the proportion of CXCR3-positive CD8
+
T lymphocytes. Human CD8
+
T lymphocytes co-cultured with human IL-27-treated astrocytes exhibited higher motility than when in contact with untreated astrocytes. These results suggested a preponderance of kinapse-like over synapse-like interactions between CD8
+
T lymphocytes and IL-27-treated astrocytes. Finally, CD8
+
T lymphocytes from MS patients showed higher motility in contact with IL-27-exposed astrocytes compared to healthy donors’ cells.
Conclusion
Our results establish that IL-27 alters the immune functions of human astrocytes and shapes the profile and motility of encountered T lymphocytes, especially CD8
+
T lymphocytes from MS patients.
•Cerebral invasive aspergillosis affecting large caliber vessels in immunocompromised patients is discussed.•Diagnosis of invasive aspergillosis may be very challenging.•Cerebral invasive ...aspergillosis may have atypical clinical presentation.•Antifungal therapy is the mainstay of medical management.•With proper follow-up, the prognosis of these patients would improve.
Invasive aspergillosis is a threat for immunocompromised patients. We present a case series of aggressive cerebral vasculitis caused by Aspergillus spp. infection in immunocompromised patients.
We present a retrospective case series of three autopsy-proven invasive cerebral aspergillosis with diffuse vasculitis affecting large caliber cerebral vessels.
Three patients were immunosuppressed: one on rituximab, one on corticosteroids, and one with a renal transplant. Two of these patients were diagnosed with cerebral aspergillosis on postmortem.
Aspergillus cerebral vasculitis is a rare form of invasive aspergillosis that should be considered in an immunocompromised individual with suggestive lesions on imaging. It should be suspected as a possible cause of aseptic neutrophil meningitis.
Cet article propose un retour sur les usages et les significations de la notion de « maison » depuis sa formulation par Claude Lévi-Strauss dans les années 1970 jusqu'aux travaux récents, aussi bien ...en anthropologie qu'en histoire de l'époque moderne. En confrontant les approches anthropologiques et leurs appropriations par les historiens de la paysannerie et de la noblesse dans la France d'Ancien Régime, cet article tente à la fois de clarifier les débats sur la notion anthropologique de « maison » et, à partir de là, de proposer des pistes pour un travail interdisciplinaire susceptible d'enrichir la compréhension de l'histoire de la noblesse comme de l'histoire de la parenté entre les XVIe et XVIIIe siècles. This essay presents a review of the uses and meanings of the concept of « house » from Lévi-Strauss's formulation in the 1970's to recent anthropological and historical researches. Through a confrontation of anthropological approaches with their appropriations by historians in their studies of peasantry and nobility in Early Modern France, this paper tries both to clarify the debates around the anthropological notion of « house » and to propose new paths for an interdisciplinary work in order to contribute to a better understanding of history of nobility as well as of history of kinship from the 16th to the 18th century.
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