Search

Abstract Background The risk of influenza infection depends on biological characteristics, individual or collective behaviors and the environmental context. The Cohorts for Pandemic Influenza (CoPanFlu) France study was set up in 2009 after the identification of the novel swine-origin A/H1N1 pandemic influenza virus. This cohort of 601 households (1450 subjects) representative for the general population aims at using an integrative approach to study the risk and characteristics of influenza infection as a complex combination of data collected from questionnaires regarding sociodemographic, medical, behavioral characteristics of subjects and indoor environment, using biological samples or environmental databases. Methods/Design Households were included between December 2009 and July 2010. The design of this study relies on systematic follow-up visits between influenza seasons and additional visits during influenza seasons, when an influenza-like illness is detected in a household via an active surveillance system. During systematic visits, a nurse collects individual and environmental data on questionnaires and obtains blood samples from all members of the household. When an influenza-like-illness is detected, a nurse visits the household three times during the 12 following days, and collects data on questionnaires regarding exposure and symptoms, and biological samples (including nasal swabs) from all subjects in the household. The end of the follow-up period is expected in fall 2012. Discussion The large amount of data collected throughout the follow-up will permit a multidisciplinary study of influenza infections. Additional data is being collected and analyzed in this ongoing cohort. The longitudinal analysis of these households will permit integrative analyses of complex phenomena such as individual, collective and environmental risk factors of infection, routes of transmission, or determinants of the immune response to infection or vaccination.

Objective: Epicardial adipose tissue (EAT) is a visceral fat that has been associated with coronary artery disease and atrial fibrillation. Previous work has revealed that EAT exhibits beige features., Methods: First, a new pan-genomic microarray analysis was performed on previously collected paired human EAT and thoracic subcutaneous AT (thSAT) from the EPICAR study (n = 31) to decipher a specific immune signature and its link with browning genes. Then, adaptive (T and B cells) and innate lymphoid cell (ILC1, ILC2, and ILC3) immunophenotyping assay panels, including CD127, CD117, and prostaglandin D2 receptor 2, were performed on prospectively collected paired human multiorgan donors (n = 18; INTERFACE study)., Results: In the EPICAR study, a positive correlation between the T helper cell subtype Th2 immune pathway and browning genes was found in EAT versus thSAT (r = 0.82; p < 0.0001). In the INTERFACE study, this correlation was also observed (r = 0.31; p = 0.017), and a preponderance of CD4 + T cells, CD8 + T cells, and a few B cells was observed in all ATs (p < 0.0001). An increase in ILCs was observed in visceral AT (VAT) (i.e., EAT + VAT; 30 ± 5 ILCs per gram of AT) compared with subcutaneous counterparts (i.e., thSAT + abdominal SAT; 8 ± 2 ILCs per gram of AT; p = 0.001), with ILC1 being the most frequent (ILC1 > ILC3 > ILC2). Numbers of ILCs per gram of AT correlated with several Th2 or browning genes (IL-13, TNF receptor superfamily member 9 [TNFRSF9], and alkaline phosphatase, biomineralization associated [ALPL]). Interestingly, a specific increase in EAT-ILC2 compared with other ATs was observed, including a significant proportion expressing CD69 and/or CD25 activation markers (97.9% ± 1.2%; p < 0.0001). Finally, more natural killer cells were observed in EAT + VAT than in thSAT + abdominal SAT (p = 0.01). Exclusion of patients with coronary artery disease in the EPICAR and INTERFACE studies did not modify the main findings. Gene expression phenotyping confirmed specific upregulation of Th2 pathway and browning genes (IL-33 and uncoupling protein 1 [UCP-1]) in EAT., Conclusions: This is the first study, to our knowledge, to provide a comparison between innate and adaptive lymphoid cells in human EAT. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging., (© 2024 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Importance: Epicardial adipose tissue (EAT) is a biologically active organ surrounding myocardium and coronary arteries that has been associated with coronary artery disease (CAD) and atrial fibrillation. Previous work has shown that EAT exhibits beige features., Objective: Our objective was to determine whether the stromal vascular fraction of the human EAT contains innate or adaptive lymphoid cells compared to thoracic subcutaneous (thSAT), visceral abdominal (VAT) and subcutaneous abdominal (abSAT)., Participants: New pangenomic microarray analysis was performed on previous transcriptomic dataset using significance analysis of microarray and ingenuity pathway analysis (n=41) to identify specific immune signature and its link with browning genes. EAT, thSAT, VAT and abSAT samples from explanted patients with severe cardiomyopathies and multi-organ donor patients (n=17) were used for flow cytometry (FC) immunophenotyping assay. Patients were on average 55±16 years-old; 47% had hypertension and 6% CAD. Phenotypic adaptive and innate immune profiles were performed using a TBNK panel and a specific ILC1-2-3 panel including CD127, CD117, CRTH2 (CD294) and activation markers such as CD25 and CD69., Results: Transcriptomic analysis showed a significant positive correlation between the TH2 immune pathway (IL-4, IL-5, IL-13, IL-25, IL-33) and browning genes (UCP-1, PRDM16, TMEM26, CITED1, TBX1) in EAT versus thSAT (R=0.82, P<0.0001). Regarding adaptive immune cells, a preponderance of CD8T cells, a contingent of CD4T cells, and a few B cells were observed in all ATs (P<0.0001). In innate lymphoid cells (ILCs), an increase was observed in visceral ATs (i.e. EAT; VAT 35±8ILCs/g of tissue) compared to their subcutaneous counterpart (i.e. thSAT+abSAT: 8±3 ILCs/g of AT, P=0.002), with a difference in the proportion of the 3 subtypes of ILCs (ILC1>ILC3>ILC2). In addition, we observed an increase in EAT-ILC2 compared to other ATs and almost all these EAT-ILC2 expressed CD69 and/or CD25 activation markers (99.75±0.16%; P<0.0001). We also observed more NKs in EAT and VAT (1520±71 cells/g of AT) than in SATs (562±17 cells/g of AT); P=0.01., Conclusion: This is the first study to provide a comparison between innate and adaptive lymphoid cells in human epicardial versus abdominal or thoracic adipose tissues. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging., Trial Registration: CODECOH No. DC-2021-4518 The French agency of biomedicine PFS21-005., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Anti-cytokine antibodies (ACA) are an emerging cause of acquired immunodeficiency, especially in previously healthy adults. The most frequently reported are anti-IFN-γ responsible for disseminated non-tuberculous mycobacteria infections, and anti-GM-CSF mainly in mycobacteria, cryptococcosis and nocardiosis infections. The presence of anti-IFN-α in severe COVID-19 infections has recently been described. The search for and detection of these ACAs in an unusual infection situation makes it possible to set up specific therapies in addition to the anti-infective treatment. ACAs are also frequent in various autoimmune pathologies where, in addition to being indicators of the breakdown of immune tolerance, they can modulate the activity of the disease according to their cytokine target. In this review of the literature, we will focus on the epidemiology and the clinical impact of these ACAs in healthy subjects and in infectious or dysimmune diseases., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Lymphocytes are essential for microbial immunity, tumor surveillance, and tissue homeostasis. However, the in vivo development and function of helper-like innate lymphoid cells (ILCs) in humans remain much less well understood than those of T, B, and NK cells. We monitored hematopoietic stem cell transplantation (HSCT) to determine the kinetics of ILC development in both children and adults. It was found that, unlike NK cells, helper-like ILCs recovered slowly, mirroring the pattern observed for T cells, with normalization achieved at 1 year. The type of graft and the proportion of CD34 + cells in the graft did not significantly affect ILC reconstitution. As HSCT is often complicated by acute or chronic graft-versus-host disease (GVHD), the potential role of ILC subsets in maintaining tissue integrity in these conditions was also analyzed. It was found that GVHD was associated with lower levels of activated and gut-homing NKp44 + ILCP, consistent with a non-redundant role of this ILC subset in preventing this life-threatening disorder in lymphopenic conditions., (©2021 Society for Leukocyte Biology.)

Objective: Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes., Methods: Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome., Results: In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes., Conclusion: Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Natural killer (NK) cells are innate cytotoxic lymphoid cells (ILCs) involved in the killing of infected and tumor cells. Among human and mouse NK cells from the spleen and blood, we previously identified by single-cell RNA sequencing (scRNAseq) two similar major subsets, NK1 and NK2. Using the same technology, we report here the identification, by single-cell RNA sequencing (scRNAseq), of three NK cell subpopulations in human bone marrow. Pseudotime analysis identified a subset of resident CD56 bright NK cells, NK0 cells, as the precursor of both circulating CD56 dim NK1-like NK cells and CD56 bright NK2-like NK cells in human bone marrow and spleen under physiological conditions. Transcriptomic profiles of bone marrow NK cells from patients with acute myeloid leukemia (AML) exhibited stress-induced repression of NK cell effector functions, highlighting the profound impact of this disease on NK cell heterogeneity. Bone marrow NK cells from AML patients exhibited reduced levels of CD160, but the CD160 high group had a significantly higher survival rate.

Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic 1 . The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes 1 . Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a-C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19.

IgG4-related disease is a chronic inflammatory disease characterized by clinical, biological and pathological unifying findings. Because these criteria are not always all together available in patients and because biological and pathological markers are not totally specific, the diagnosis should be retained after exclusion of mimickers. Since the individualization of IgG4-RD, several studies have allowed to better characterize immunological abnormalities associated with this particular condition. B and T cell oligoclonal activation is associated with T helper 2 cytokine production leading to IgG4 production and profibrotic cytokine release. A central role for T follicular helper 2 cells is suggested from recent findings. We summarize here recent advances in understanding of immune abnormalities in IgG4-related disease., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Septic shock, a major cause of death in critical care, is the clinical translation of a cytokine storm in response to infection. It can be complicated by sepsis-induced immunosuppression, exemplified by blood lymphopenia, an excess of circulating Treg lymphocytes, and decreased HLA-DR expression on circulating monocytes. Such immunosuppression is associated with secondary infections, and higher mortality. The effect of these biological modifications on circulating innate lymphoid cells (ILCs) has been little studied. Methods: We prospectively enrolled patients with septic shock (Sepsis-3 definition) in the intensive care unit (ICU) of Timone CHU Hospital. ICU controls (trauma, cardiac arrest, neurological dysfunction) were recruited at the same time (NCT03297203). We performed immunophenotyping of adaptive lymphocytes (CD3 + T cells, CD19 + B cells, CD4 + CD25 + FoxP3 + Treg lymphocytes), ILCs (CD3 - CD56 + NK cells and helper ILCs - ILC1, ILC2, and ILC3), and monocytes by flow cytometry on fresh blood samples collected between 24 and 72 h after admission. Results: We investigated adaptive and innate circulating lymphoid cells in the peripheral blood of 18 patients in septic shock, 15 ICU controls, and 30 healthy subjects. As expected, the peripheral blood lymphocytes of all ICU patients showed lymphopenia, which was not specific to sepsis, whereas those of the healthy volunteers did not. Circulating CD3 + T cells and CD3 - CD56 + NK cells were mainly concerned. There was a tendency toward fewer Treg lymphocytes and lower HLA-DR expression on monocytes in ICU patients with sepsis. Although the ILC1 count was higher in septic patients than healthy subjects, ILC2, and ILC3 counts were lower in both ICU groups. However, ILC3s within the total ILCs were overrepresented in patients with septic shock. The depression of immune responses has been correlated with the occurrence of secondary infections. We did not find any differences in ILC distribution according to this criterion. Conclusion: All ICU patients exhibit lymphopenia, regardless of the nature (septic or sterile) of the initial medical condition. Specific distribution of circulating ILCs, with an excess of ILC1, and a lack of ILC3, may characterize septic shock during the first 3 days of the disease., (Copyright © 2019 Carvelli, Piperoglou, Bourenne, Farnarier, Banzet, Demerlé, Gainnier and Vély.)

Natural killer (NK) cells are innate lymphoid cells (ILCs) involved in antimicrobial and antitumoral responses. Several NK cell subsets have been reported in humans and mice, but their heterogeneity across organs and species remains poorly characterized. We assessed the diversity of human and mouse NK cells by single-cell RNA sequencing on thousands of individual cells isolated from spleen and blood. Unbiased transcriptional clustering revealed two distinct signatures differentiating between splenic and blood NK cells. This analysis at single-cell resolution identified three subpopulations in mouse spleen and four in human spleen, and two subsets each in mouse and human blood. A comparison of transcriptomic profiles within and between species highlighted the similarity of the two major subsets, NK1 and NK2, across organs and species. This unbiased approach provides insight into the biology of NK cells and establishes a rationale for the translation of mouse studies to human physiology and disease., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The syndromic diarrhea/trichohepatoenteric syndrome (SD/THE) is a rare and multi-system genetic disorder caused by mutation in SKIV2L or in TTC37 , two genes encoding subunits of the putative human SKI complex involved in RNA degradation. The main features are intractable diarrhea of infancy, hair abnormalities, facial dysmorphism, and intrauterine growth restriction. Immunologically this syndrome is associated with a hypogammaglobulinemia leading to an immunoglobulin supplementation. Our immune evaluation of a large French cohort of SD/THE patient revealed several immunological defects. First, switched memory B lymphocytes count is very low. Second, IFN-γ production by T and NK cells is impaired and associated with a reduced degranulation of NK cells. Third, T cell proliferation was abnormal in 3/6 TTC37 -mutated patients. These three patients present with severe EBV infection and a transient hemophagocytosis which may be related to these immunological defects. Moreover, an immunological screening of patients with clinical features of SD/THE could facilitate both diagnosis and therapeutic management of these patients.

Recent years have seen a marked increase in our understanding of innate lymphoid cells (ILCs). ILCs can be classified into different groups based on their similarity to T cell subsets in terms of their expression of key transcription factors and cytokine production. Various immunological functions of ILCs have been described, and increasing numbers of studies have implicated these cells in inflammatory disorders. Here, we detail the roles of ILCs in inflammatory diseases; we cover type 2 inflammatory diseases (such as asthma, chronic rhinosinusitis and atopic dermatitis), as well as inflammatory bowel diseases, psoriasis and other systemic or organ-specific inflammatory and autoimmune diseases. Future directions in the field are discussed, together with potential avenues of treatment.

Over 60% of human melanoma tumors bear a mutation in the BRAF gene. The most frequent mutation is a substitution at codon 600 (V600E), leading to a constitutively active BRAF and overactivation of the MAPK pathway. Patients harboring mutated BRAF respond to kinase inhibitors such as vemurafenib. However, these responses are transient, and relapses are frequent. Melanoma cells are efficiently lysed by activated natural killer (NK) cells. Melanoma cells express several stress-induced ligands that are recognized by activating NK-cell receptors. We have investigated the effect of vemurafenib on the immunogenicity of seven BRAF -mutated melanoma cells to NK cells and on their growth and sensitivity to NK-cell-mediated lysis. We showed that vemurafenib treatment modulated expression of ligands for two activating NK receptors, increasing expression of B7-H6, a ligand for NKp30, and decreasing expression of MICA and ULBP2, ligands for NKG2D. Vemurafenib also increased expression of HLA class I and HLA-E molecules, likely leading to higher engagement of inhibitory receptors (KIRs and NKG2A, respectively), and decreased lysis of vemurafenib-treated melanoma cell lines by cytokine-activated NK cells. Finally, we showed that whereas batimastat (a broad-spectrum matrix metalloprotease inhibitor) increased cell surface ULBP2 by reducing its shedding, vemurafenib lowered soluble ULBP2, indicating that BRAF signal inhibition diminished expression of both cell-surface and soluble forms of NKG2D ligands. Vemurafenib, inhibiting BRAF signaling, shifted the balance of activatory and inhibitory NK ligands on melanoma cells and displayed immunoregulatory effects on NK-cell functional activities. Cancer Immunol Res; 5(7); 582-93. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Inborn errors of DNA repair or replication underlie a variety of clinical phenotypes. We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency. Four of the 5 patients also had postnatal growth retardation. The association of neutropenia and NK cell deficiency, which is unusual among primary immunodeficiencies and bone marrow failures, was due to a blockade in the bone marrow and was mildly symptomatic. We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients. The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice. The patients' fibroblasts displayed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which was rescued by WT GINS1. The residual levels of GINS1 activity reached 3% to 16% in patients' cells, depending on their GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype. The levels of GINS1 activity did not influence the immunological phenotype, which was uniform. Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency.

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder involving virtually every organ with a risk of organ dysfunction. Despite recent studies regarding B cell and T cell compartments, the disease's pathophysiology remains poorly understood. We examined and characterized subsets of circulating lymphocytes in untreated patients with active IgG4-RD. Twenty-eight consecutive patients with biopsy-proven IgG4-RD were included in a prospective, multicentric study. Lymphocytes' subsets were analyzed by flow cytometry, with analysis of T H 1/T H 2/T H 17, T FH cells, and cytokine release by peripheral blood mononuclear cells. Results were compared to healthy controls and to patients with primary Sjögren's syndrome. Patients with IgG4-RD showed an increase of circulating T regulatory, T H 2, T H 17, and CD4 + CXCR5 + PD1 + T FH cell subsets. Accordingly, increased levels of IL-10 and IL-4 were measured in IgG-RD patients. T FH increase was characterized by the specific expansion of T FH 2 (CCR6 - CXCR3 - ), and to a lesser extent of T FH 17 (CCR6 + CXCR3 - ) cells. Interestingly, CD4 + CXCR5 + PD1 + T FH cells normalized under treatment. IgG4-RD is characterized by a shift of circulating T cells toward a T H 2/T FH 2 and T H 17/T FH 17 polarization. This immunological imbalance might be implicated in the disease's pathophysiology. Treatment regimens targeting such T cells warrant further evaluation.

Programmed Death-1 (PD-1), an inhibitory receptor expressed by activated lymphocytes, is involved in regulating T- and B-cell responses. PD-1 and its ligands are exploited by a variety of cancers to facilitate tumor escape through PD-1-mediated functional exhaustion of effector T cells. Here, we report that PD-1 is upregulated on Natural Killer (NK) cells from patients with Kaposi sarcoma (KS). PD-1 was expressed in a sub-population of activated, mature CD56dimCD16pos NK cells with otherwise normal expression of NK surface receptors. PD-1pos NK cells from KS patients were hyporesponsive ex vivo following direct triggering of NKp30, NKp46 or CD16 activating receptors, or short stimulation with NK cell targets. PD-1pos NK cells failed to degranulate and release IFNγ, but exogenous IL-2 or IL-15 restored this defect. That PD-1 contributed to NK cell functional impairment and was not simply a marker of dysfunctional NK cells was confirmed in PD-1-transduced NKL cells. In vitro, PD-1 was induced at the surface of healthy control NK cells upon prolonged contact with cells expressing activating ligands, i.e. a condition mimicking persistent stimulation by tumor cells. Thus, PD-1 appears to plays a critical role in mediating NK cell exhaustion. The existence of this negative checkpoint fine-tuning NK activation highlights the possibility that manipulation of the PD-1 pathway may be a strategy for circumventing tumor escape not only from the T cell-, but also the NK-cell mediated immune surveillance.

Antibodies have been shown to block signaling through cell surface receptors using several mechanisms. The two most common are binding to the ligand-binding site of the receptor and, conversely, binding to the receptor-binding site of the ligand. Here, we investigated the inhibitory mechanism of an antibody (17B1.3) against human B7-H6, a stress-induced cellular ligand for the natural killer (NK) cell receptor NKp30. Binding of this antibody to B7-H6, a transmembrane protein expressed on tumor and other stressed cells, but not on normal cells, prevents NK cell activation via NKp30. We determined the crystal structure of antibody 17B1.3 in complex with the ectodomain of B7-H6 to 2.5Å resolution. Surprisingly, 17B1.3 binds to a site on B7-H6 that is completely distinct from the binding site for NKp30, such that 17B1.3 does not block the NKp30-B7-H6 interaction. We then asked whether 17B1.3 prevents signaling by binding to a putative site for B7-H6 dimerization. However, structure-based mutations designed to disrupt potential B7-H6 dimerization through this site did not diminish NKp30-mediated cell activation. We conclude that the bulky 17B1.3 antibody most likely acts by sterically interfering with close cell-cell contacts at the NK cell-target cell interface that are required for NK cell activation. A similar inhibitory mechanism may apply to other antibodies, including therapeutic antibodies that block signaling through cell surface receptors whose ligands are also cell surface proteins., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved., Competing Interests: E.V. is the cofounder of and a shareholder in Innate Pharma. The other authors have no conflicting financial interest to declare.

Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (ΔBC low ) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This ΔBC low blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-α and anti-TRAIL mAb which reinstated innate immunity.

Natural Killer (NK) cells have been shown to exert antiviral and antitumoural activities. Nevertheless most available data are derived from mouse models and functions of these cells in human remain unclear. To evaluate the impact of low circulating NK cell counts and to provide some clues to the role of NK cells in natural conditions, we studied a large cohort of patients with common variable immunodeficiency (CVID) included in a multicenter cohort of patients with primary hypogammaglobulinaemia. Patients were classified into three groups on the basis of their NK cell counts: severe and mild NK cell lymphopenia (<50 and 50-99×10(6)/L respectively), and normal NK cell counts (>100×10(6)/L). Clinical events were analyzed and compared between these three groups of patients. During study period, 457 CVID patients were included: 99 (21.7%) with severe NK cell lymphopenia, 118 (25.8%) with mild NK cell lymphopenia and 240 (52.5%) with normal NK cell counts. Non-infectious complications (57% vs. 36% and 35%), and, particularly, granulomatous complications (25.3% vs. 13.6% and 8.8%), were more frequent in patients with severe NK cell lymphopenia than in other groups. Invasive infections (68.7% vs. 60.2% and 48.8%), including bacteraemia (22.2% vs. 5.9% and 8.3%) and infectious pneumonia (63.6% vs. 59.3% and 44.2%), were also more frequent in this population. However, no difference was observed for viral infections and neoplasms. Low circulating NK cell counts are associated with more severe phenotypes of CVID, which may indicate a protective role of these immune cells against severe bacterial infections and other complications and non-redundant immune functions when the adaptive immune response is not optimal., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

The world of lymphocytes has recently expanded. A group of cells, innate lymphoid cells (ILC), has been defined. It includes lymphoid cells that have been known for decades, such as natural killer (NK) cells and lymphoid tissue-inducer (LTi) cells. NK cells recognize a vast array of tumor cells, which they help to eliminate through cytotoxicity and the production of cytokines, such as IFNγ. Advances in our understanding of NK-cell biology have led to a growing interest in the clinical manipulation of these cells in cancer. The other ILCs are found mostly in the mucosae and mucosal-associated lymphoid tissues, where they rapidly initiate immune responses to pathogens without the need for specific sensitization. Here, we outline the basic features of ILCs and review the role of ILCs other than NK cells in cancer. Much of the role of these ILCs in cancer remains unknown, but several findings should lead to further efforts to dissect the contribution of different ILC subsets to the promotion, maintenance, or elimination of tumors at various anatomic sites. This will require the development of standardized reagents and protocols for monitoring the presence and function of ILCs in human blood and tissue samples., (©2015 American Association for Cancer Research.)

Dendritic cell-derived exosomes (Dex) are small extracellular vesicles secreted by viable dendritic cells. In the two phase-I trials that we conducted using the first generation of Dex (IFN-γ-free) in end-stage cancer, we reported that Dex exerted natural killer (NK) cell effector functions in patients. A second generation of Dex (IFN-γ-Dex) was manufactured with the aim of boosting NK and T cell immune responses. We carried out a phase II clinical trial testing the clinical benefit of IFN-γ-Dex loaded with MHC class I- and class II-restricted cancer antigens as maintenance immunotherapy after induction chemotherapy in patients bearing inoperable non-small cell lung cancer (NSCLC) without tumor progression. The primary endpoint was to observe at least 50% of patients with progression-free survival (PFS) at 4 mo after chemotherapy cessation. Twenty-two patients received IFN-γ-Dex. One patient exhibited a grade three hepatotoxicity. The median time to progression was 2.2 mo and median overall survival (OS) was 15 mo. Seven patients (32%) experienced stabilization of >4 mo. The primary endpoint was not reached. An increase in NKp30-dependent NK cell functions were evidenced in a fraction of these NSCLC patients presenting with defective NKp30 expression. Importantly, MHC class II expression levels of the final IFN-γ-Dex product correlated with expression levels of the NKp30 ligand BAG6 on Dex, and with NKp30-dependent NK functions, the latter being associated with longer progression-free survival. This phase II trial confirmed the capacity of Dex to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC.