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Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of theJCI, Cao and colleagues found that a sensor of endoplasmic reticulum (ER) stress, the inositol-requiring kinase 1[alpha]/X-box-binding protein 1 (IRE1[alpha]/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1[alpha] and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn's disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease., The IRE1[alpha]/XBP1 pathway prevents unresolved ER stress in ILC3s Innate immune cells ensure organismal homeostatic functions and immune surveillance by rapidly triggering specialized effector functions in response to changes in [...]

The immune system can control cancer progression. However, even though some innate immune sensors of cellular stress are expressed intrinsically in epithelial cells, their potential role in cancer aggressiveness and subsequent overall survival in humans is mainly unknown. Here, we show that nucleotide-binding oligomerization domain-like receptor (NLR) family CARD domain-containing 4 (NLRC4) is downregulated in epithelial tumor cells of patients with colorectal cancer (CRC) by using spatial tissue imaging. Strikingly, only the loss of tumor NLRC4, but not stromal NLRC4, was associated with poor immune infiltration (mainly DCs and [CD4.sup.+] and [CD8.sup.+] T cells) and accurately predicted progression to metastatic stage IV and decrease in overall survival. By combining multiomics approaches, we show that restoring NLRC4 expression in human CRC cells triggered a broad inflammasome-independent immune reprogramming consisting of type I interferon (IFN) signaling genes and the release of chemokines and myeloid growth factors involved in the tumor infiltration and activation of DCs and T cells. Consistently, such reprogramming in cancer cells was sufficient to directly induce maturation of human DCs toward a Th1 antitumor immune response through IL-12 production in vitro. In multiple human carcinomas (colorectal, lung, and skin), we confirmed that NLRC4 expression in patient tumors was strongly associated with type I IFN genes, immune infiltrates, and high microsatellite instability. Thus, we shed light on the epithelial innate immune sensor NLRC4 as a therapeutic target to promote an efficient antitumor immune response against the aggressiveness of various carcinomas., Introduction Higher vertebrates have developed innate protective mechanisms that can detect stress-induced cues triggered by infection, injury, or carcinogenesis. One example of cytosolic sensors of cellular perturbations are the nucleotide-binding [...]

Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP affects risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected. To better characterize the pathways of susceptibility, we challenged hematopoietic Tet Methylcytosine Dioxygenase 2-knockout ([Tet2.sup.-/-]) and floxed control mice ([Tet2.sup.fl/fl]) with Streptococcus pneumoniae. As with human CHIP carriers, [Tet2.sup.-/-] mice had hematopoietic abnormalities resulting in the expansion of inflammatory monocytes and neutrophils in peripheral blood. Yet, these cells were insufficient in defending against S. pneumoniae and resulted in increased pathology, impaired bacterial clearance, and higher mortality in [Tet2.sup.-/-] mice. We delineated the transcriptional landscape of [Tet2.sup.-/-] neutrophils and found that, while inflammation-related pathways were upregulated in [Tet2.sup.-/-] neutrophils, migration and motility pathways were compromised. Using live-imaging techniques, we demonstrated impairments in motility, pathogen uptake, and neutrophil extracellular trap (NET) formation by [Tet2.sup.-/-] neutrophils. Collectively, we show that CHIP is a risk factor for bacterial pneumonia related to innate immune impairments., Introduction Human aging is accompanied by dysregulation of hematopoiesis in the bone marrow (BM), which may have adverse clinical consequences (1). Hematopoiesis is a tightly regulated process by which hematopoietic [...]

Background Compared with the general population, the immune response to COVID-19 mRNA vaccines is lower in adult kidney transplant recipients (KTRs). However, data is limited for pediatric KTRs. In this study, we aimed to assess humoral and cellular immune responses to the COVID-19 mRNA vaccine in pediatric KTRs. Methods This multicenter, prospective, case-control study included 63 KTRs (37 male, aged 12-21 years), 19 dialysis patients, and 19 controls. Humoral (anti-SARS-CoV2 IgG, neutralizing Ab (nAb)) and cellular (interferon-gamma release assay (IGRA)) immune responses were assessed at least one month after two doses of BNT162b2 mRNA vaccine. Results Among COVID-19 naïve KTRs (n = 46), 76.1% tested positive for anti-SARS-CoV-2 IgG, 54.3% for nAb, and 63% for IGRA. Serum levels of anti-SARS-CoV-2 IgG and nAb activity were significantly lower in KTRs compared to dialysis and control groups (p < 0.05 for all). Seropositivity in KTRs was independently associated with shorter transplant duration (p = 0.005), and higher eGFR (p = 0.007). IGRA titer was significantly lower than dialysis patients (p = 0.009). Twenty (43.4%) KTRs were positive for all immune parameters. Only four of 11 seronegative KTRs were IGRA-positive. COVID-19 recovered KTRs had significantly higher anti-SARS-CoV-2 IgG and nAb activity levels than COVID-19 naïve KTRs (p = 0.018 and p = 0.007, respectively). Conclusions The humoral and cellular immune responses to SARS-CoV-2 mRNA BNT162b2 vaccine are lower in pediatric KTRs compared to dialysis patients. Further prospective studies are required to demonstrate the clinical efficacy of the mRNA vaccine in KTRs. This prospective study was registered in ClinicalTrials.gov (NCT05465863, registered retrospectively at 20.07.2022). Graphical abstract, Author(s): Ruveyda Gulmez [sup.1] , Dogukan Ozbey [sup.2] , Ayse Agbas [sup.1] , Bagdagul Aksu [sup.3] [sup.4] , Nurdan Yildiz [sup.5] , Diana Uckardes [sup.6] , Seha Saygili [sup.1] , [...]

Background Data on humoral immune response to standard COVID-19 vaccination are scarce in adolescent patients and lacking for children below 12 years of age with chronic kidney disease including kidney transplant recipients. Methods We therefore investigated in this retrospective two-center study (DRKS00024668; registered 23.03.2021) the humoral immune response to a standard two-dose mRNA vaccine regimen in 123 CKD patients aged 5-30 years. A live-virus assay was used to assess the serum neutralizing activity against the SARS-CoV-2 omicron (BA.1) variant. Results Children aged 5-11 years had a comparable rate and degree of immune response to adolescents despite lower vaccine doses (10 [micro]g vs. 30 [micro]g BNT162b2). Treatment with two (odds ratio 9.24) or three or more (odds ratio 17.07) immunosuppressants was an independent risk factor for nonresponse. The immune response differed significantly among three patient cohorts: 48 of 77 (62.3%) kidney transplant recipients, 21 of 26 (80.8%) patients on immunosuppressive therapy, and 19 of 20 (95.0%) patients with chronic kidney disease without immunosuppressive therapy responded. In the kidney transplant recipients, immunosuppressive regimens comprising mycophenolate mofetil, an eGFR of 1411 BAU/mL, respectively, showed a neutralization activity against the omicron variant. Conclusion A standard mRNA vaccine regimen in immunosuppressed children and adolescents with kidney disease elicits an attenuated humoral immune response with effective live virus neutralization against the omicron variant in approximately 10% of the patients, underlying the need for omicron-adapted vaccination. Graphical abstract, Author(s): Maximilian Stich [sup.1] , Veronica Di Cristanziano [sup.2] , Burkhard Tönshoff [sup.1] , Lutz Thorsten Weber [sup.3] , Jörg Dötsch [sup.3] , Marian Theodor Rammer [sup.3] , Susanne Rieger [...]

SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis-related genes. Further, robust basal stem cell activation contributed to neuroepithelial regeneration and restored ACE2 expression postinfection. Together, our study characterized the nasal tropism of SARS- CoV-2 strains, immune clearance, and regeneration after infection. The shifting characteristics of viral infection at the airway portal provide insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention., Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen in the worldwide pandemic of coronavirus disease 2019 (COVID-19), is readily transmitted via respiratory droplets during close contact. The [...]

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-[gamma] secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-[gamma] in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-[gamma]-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy., Introduction The influence of inflammation on various aspects of immune responses is recognized, yet the extent of these effects remains largely unknown. This is especially true within clinical contexts in [...]

BACKGROUND. Precise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy. METHODS. We measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay. RESULTS. Nonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral [CD8.sup.+] T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors. CONCLUSION. Combinations of soluble immune factors might be able to identify patients unlikely to respond to PD- 1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC. TRIAL REGISTRATION. UMIN000019674. FUNDING. This study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation., Introduction Targeting of the immune system has provided clinical benefit for individuals with advanced solid tumors, including non-small cell lung cancer (NSCLC) (1). Currently approved immune-checkpoint inhibitors (ICIs) include monoclonal [...]

Radiotherapy (RT) is considered immunogenic, but clinical data demonstrating RT-induced T cell priming are scarce. Here, we show in a mouse tumor model representative of human lymphocyte-depleted cancer that RT enhanced spontaneous priming of thymus-derived ([FOXP3.sup.+][Helios.sup.+]) Tregs by the tumor. These Tregs acquired an effector phenotype, populated the tumor, and impeded tumor control by a simultaneous, RT-induced [CD8.sup.+] cytotoxic T cell (CTL) response. Combination of RT with CTLA-4 or PD-1 blockade, which enables CD28 costimulation, further increased this Treg response and failed to improve tumor control. We discovered that upon RT, the CD28 ligands CD86 and CD80 differentially affected the Treg response. CD86, but not CD80, blockade prevented the effector Treg response, enriched the tumor-draining lymph node migratory conventional DCs that were positive for PD-L1 and CD80 ([PD-L1.sup.+][CD80.sup.+]), and promoted CTL priming. Blockade of CD86 alone or in combination with PD-1 enhanced intratumoral CTL accumulation, and the combination significantly increased RT-induced tumor regression and OS. We advise that combining RT with PD-1 and/or CTLA-4 blockade may be counterproductive in lymphocyte-depleted cancers, since these interventions drive Treg responses in this context. However, combining RT with CD86 blockade may promote the control of such tumors by enabling a CTL response., Introduction Immunotherapy by antibody-based immune checkpoint blockade (ICB) is a new treatment modality for multiple cancer types. However, only a minority of patients experience durable clinical responses (1), partly due [...]

Background COVID-19 disease in kidney transplant (KT) recipients is associated with increased morbidity, mortality, and hospitalization rates. Unfortunately, KT recipients also have a reduced response to SARS-CoV-2 immunization. The primary aim of this study was to assess immunologic response to SARS-CoV-2 mRNA vaccines in pediatric kidney transplant recipients 12-18 years of age. Secondary aims were to assess response rates following a third immunization and determine factors that influence immunization response. Methods Pediatric KT recipients in a single tertiary center received SARS-CoV-2 mRNA vaccination as per local protocol. SARS-CoV-2 immunoglobulin (IgG) was measured following second and/or third vaccination. Demographics including patient factors (age, gender, and underlying disease), transplant factors (time and type of transplant), and immunosuppression (induction, maintenance, and immunomodulatory therapies such as IVIG) were collected from the medical records. Results Of 20 participants, 10 (50%) responded following a two-dose vaccine schedule, which increased to 15 (75%) after three doses. Maintenance immunosuppression affected immunologic response, with azathioprine demonstrating a higher rate of response to vaccine compared to mycophenolate (100% vs. 38%, p = 0.04). Increasing prednisolone dose had a negative impact on immunologic response (0.01 mg/kg/day increase: OR 1.60 95% CI 1.01 to 2.57). Tacrolimus dose and trough levels, age, time post-transplant, underlying disease, and other immunosuppression did not impact immunologic response. Conclusions Pediatric KT recipients had similar response rates following SARS-CoV-2 immunization as adult KT recipients. Immunologic response improved following a third immunization. Choice of antimetabolite and prednisolone dosing influenced the rate of response. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary Information, Author(s): Rachael F. Kermond [sup.1] , Justyna E. Ozimek-Kulik [sup.1] [sup.2] , Siah Kim [sup.1] [sup.3] [sup.4] , Stephen I. Alexander [sup.1] [sup.3] [sup.5] , Deirdre Hahn [sup.1] , Alison [...]

Author(s): Rolando Claure-Del Granado [sup.1] [sup.2] , Matthew T. James [sup.3] , Matthieu Legrand [sup.4] Author Affiliations: (1) Division of Nephrology, Hospital Obrero No 2-Caja Nacional de Salud, , Cochabamba, [...]

Background: The increasing prevalence of food sensitivities has been attributed to changes in gut microenvironment; however, ubiquitous environmental triggers such as inorganic nanoparticles (NPs) used as food additives have not been thoroughly investigated. Objectives: We explored the impact of the NP-structured food-grade silicon dioxide (fg-Si[O.sub.2]) on intestinal immune response involved in oral tolerance (OT) induction and evaluated the consequences of oral chronic exposure to this food-additive using a mouse model of OT to ovalbumin (OVA) and on gluten immunopathology in mice expressing the celiac disease risk gene, HLA-DQ8. Methods: Viability, proliferation, and cytokine production of mesenteric lymph node (MLN) cells were evaluated after exposure to fg-Si[O.sub.2]. C57BL/6J mice and a mouse model of OT to OVA were orally exposed to fg- Si[O.sub.2] or vehicle for 60 d. Fecal lipocalin-2 (Lcn-2), anti-OVA IgG, cytokine production, and immune cell populations were analyzed. Nonobese diabetic (NOD) mice expressing HLA-DQ8 (NOD/DQ8), exposed to fg-Si[O.sub.2] or vehicle, were immunized with gluten and immunopathology was investigated. Results: MLN cells exposed to fg-Si[O.sub.2] presented less proliferative T cells and lower secretion of interleukin 10 (IL-10) and transforming growth factor beta (TGF-[beta]) by T regulatory and [CD45.sup.+] [CD11b.sup.+] [CD103.sup.+] cells compared to control, two factors mediating OT. Mice given fg-Si[O.sub.2] exhibited intestinal Lcn-2 level and interferon gamma (IFN-[gamma]) secretion, showing inflammation and less production of IL-10 and TGF-[beta]. These effects were also observed in OVA-tolerized mice exposed to fg-Si[O.sub.2], in addition to a breakdown of OT and a lower intestinal frequency of T cells. In NOD/DQ8 mice immunized with gluten, the villus-to-crypt ratio was decreased while the [CD3.sup.+] intraepithelial lymphocyte counts and the Th1 inflammatory response were aggravated after fg-Si[O.sub.2] treatment. Discussion: Our results suggest that chronic oral exposure to fg-Si[O.sub.2] blocked oral tolerance induction to OVA, and worsened gluten-induced immunopathology in NOD/DQ8 mice. The results should prompt investigation on the link between Si[O.sub.2] exposure and food sensitivities in humans. https://doi.org/10.1289/EHP12758, Introduction Adverse food reactions include food sensitivities, which are immune mediated, and food intolerance, which is the result of failure to digest the triggering agent, as in lactose intolerance. (1,2) [...]

Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti-programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression, and the combination of PD- 1H blockade with anti-PD therapy conferred a synergistic antileukemia effect. Our findings provide the basis for PD- 1H as a potential therapeutic target for treating human AML., Introduction Acute myeloid leukemia (AML) is a heterogenous clonal disorder that is characterized by uncontrolled clonal expansion of myeloid progenitor cells (blasts) that leads to BM failure (1). AML is [...]

Although most [CD8.sup.+] T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self- peptides. Recognition and elimination of pathogenic target cells that express these Qa-1- self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression. Immunization with synthetic agonist peptides that mobilize CD8 Tregs in vivo efficiently inhibit antigraft antibody responses and markedly prolong heart and kidney organ graft survival. Definition of TCR-dependent differentiation and target recognition by this lineage of CD8 Tregs may open the way to new therapeutic approaches to inhibit pathogenic antibody responses., Introduction The immune system has evolved complex mechanisms that allow efficient destruction of microbial pathogens while sparing the host's own tissues. Maintenance of this balance depends, in part, on regulatory [...]

COVID-19 clinical manifestations range from asymptomatic infection to death. Whether prior immune responses to human coronaviruses affect responses to SARS-CoV-2 remains unclear. At the population level, disparities in COVID-19 outcomes [...]

Background Bacterial ghost cells (BGCs) are cells were drained of their genetic and cytoplasmic components. This work aimed to develop vaccine candidates against the Shigella flexneri (S. flexneri) 2b serotype using the BGCs approach. For the first time, (S. flexneri) 2b serotype BGCs vaccine was prepared by incubation with Triton X-100 (TX100) for only 12 h. Its safety and immunogenicity were compared to another vaccine produced using a previously used surfactant, namely Tween 80 (TW80). Scanning electron microscopy (SEM), cellular DNA, protein contents measurements, and ghost cell re-cultivation were used to confirm the successful generation of the BGCs. Immunogenicity was assessed through mice's intraperitoneal (IP) immunization followed by infection with S. flexneri ATCC 12022. Finally, histopathological examination was carried out. Results Viable colony forming units (CFUs) of S. flexneri were counted from stool samples as well as homogenized colon tissues of the non-immunized challenged group. Immunized mice sera showed a significant increase in serum bactericidal activity of both preparations (TX100 = 40% and TW80 = 56%) compared to the non-immunized challenged group (positive control). The IgG levels of the bacterial ghost-vaccinated groups were four and three times greater for the TX100 and TW80 ghost vaccines, respectively, compared to that of the positive control; both bacterial ghost vaccines (BGVs) were safe and effective, according to the results of the safety check tests and histopathological analysis. Conclusions When comparing the BGVs prepared using TX100 and TW80 methods, the use of TX100 as a new chemical treating agent for BGC production attained robust results in terms of shorter incubation time with the targeted cells and a strong immune response against S. flexneri 2b serotype ATCC 12022 in the IP challenge test. However, a clinical study is needed to confirm the efficacy and total safety of this novel vaccine. Keywords: Shigella flexneri, Triton X-100, Bacterial ghost vaccine, Shigellosis, Immune response, Bactericidal activity, Histopathology analysis, Author(s): Amany Abdelfattah[sup.1], Reham Samir[sup.2] and Heba M. Amin[sup.1] Background Shigella flexneri (S. flexneri) is one of the four Shigella species and a non-lactose fermenter member of the Enterobacteriaceae family. [...]