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Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The human uterus undergoes constant regeneration and is exposed to distinct environmental factors. To assess uterine immune system variation, we performed a system-level analysis of endometrial and peripheral blood immune cells in monozygotic twins. Although most immune cell phenotypes in peripheral blood showed high genetic heritability, more variation was found in endometrial immune cells, indicating a stronger influence by environmental factors. Cytomegalovirus infection was identified to influence peripheral blood immune cell variability but had limited effect on endometrial immune cells. Instead, hormonal contraception shaped the local endometrial milieu and immune cell composition with minor influence on the systemic immune system. These results highlight that the magnitude of human immune system variation and factors influencing it can be tissue specific. Editor's summary: Baseline differences in the immune system between individuals are driven by both heritable and nonheritable, environmental factors. By analyzing endometrial and peripheral blood immune cells collected from monozygotic twins, Bister et al. measured the tissue-specific contributions of nonheritable effects on immune system variation. Although peripheral blood immune cells were largely shaped by genetics, environmental factors including hormonal contraception contributed more strongly to the variation in endometrial immune cells and soluble proteome. Together, these findings demonstrate that the human immune system can be highly variable and driven by nonheritable factors in a tissue-specific manner. —Claire Olingy [ABSTRACT FROM AUTHOR]

Host–microbiome interplay from birth is essential for immune imprinting and tuning. Live gut microbes and microbial‐derived metabolites regulate the development and modulation of the immune system, but whether microbial metabolites solely are sufficient to induce immune maturation remains unclear. Sterile faecal filtrates (FFT) were generated from murine gut contents. Newborn germ‐free (GF) mice were treated twice daily with FFT (GF‐FFT) or saline (GF‐NaCl) from post‐natal day 5 until 4 weeks of age. A third group of GF neonates were conventionalized by the transfer of caecal microbiota with live gut microbes. Host immune compartments were comprehensively immunophenotyped and systemically analysed in all available immune‐related organs using flow cytometry. Oral FFT was associated with reduced survival among neonates (n = 7/19; 36.8% mortality), while saline treatment was well tolerated (n = 1/17, 5.9% mortality). Four‐week‐old FFT‐treated pups were comparable in body weight to GF‐NaCl, and the major B‐cell, conventional T‐cell and unconventional T‐cell subsets were unchanged from saline‐treated mice. Live bacteria administered during early life induced clear changes in proportions of B cells, T cells and T‐cell subsets in all mucosal tissues and secondary lymphoid organs compared to GF‐FFT, including restoration of intestinal natural killer T (NKT) cells with characteristics similar to conventional pups. Our findings show that oral administration of a FFT made of microbial metabolites, antigens and bacteriophages alone is insufficient to induce normal immune development elicited by the presence of live bacteria. Reduced survival during neonatal FFT treatment suggests a potential bioactive attribute of sterile faecal filtrates. [ABSTRACT FROM AUTHOR]

Author(s): Martina Molgora [1]; Eduardo Bonavita [1]; Andrea Ponzetta [1]; Federica Riva [2]; Marialuisa Barbagallo [1]; Sbastien Jaillon [1, 3]; Branka Popovi [4]; Giovanni Bernardini [5, 6]; Elena Magrini [1]; [...]

Adipose tissue inflammation is a driving factor for the development of obesity‐associated metabolic disturbances, and a role of adipose tissue T cells in initiating the pro‐inflammatory signaling is emerging. However, data on human adipose tissue T cells in obesity are limited, reflected by the lack of phenotypic markers to define tissue‐resident T cell subsets. In this study, we performed a deep characterization of T cells in blood and adipose tissue depots using multicolor flow cytometry and RNA sequencing. We identified distinct subsets of T cells associated with obesity expressing the activation markers, CD26 and CCR5, and obesity‐specific genes that are potentially engaged in activating pro‐inflammatory pathway, including ceramide signaling, autophagy, and IL‐6 signaling. These findings increase our knowledge on the heterogeneity of T cells in adipose tissue and on subsets that may play a role in obesity‐related pathogenesis. [ABSTRACT FROM AUTHOR]

Corona disease 2019 (COVID‐19) affects multiple organ systems. Recent studies have indicated perturbations in the circulating metabolome linked to COVID‐19 severity. However, several questions pertain with respect to the metabolome in COVID‐19. We performed an in‐depth assessment of 1129 unique metabolites in 27 hospitalized COVID‐19 patients and integrated results with large‐scale proteomic and immunology data to capture multiorgan system perturbations. More than half of the detected metabolic alterations in COVID‐19 were driven by patient‐specific confounding factors ranging from comorbidities to xenobiotic substances. Systematically adjusting for this, a COVID‐19‐specific metabolic imprint was defined which, over time, underwent a switch in response to severe acute respiratory syndrome coronavirus‐2 seroconversion. Integration of the COVID‐19 metabolome with clinical, cellular, molecular, and immunological severity scales further revealed a network of metabolic trajectories aligned with multiple pathways for immune activation, and organ damage including neurological inflammation and damage. Altogether, this resource refines our understanding of the multiorgan system perturbations in severe COVID‐19 patients. [ABSTRACT FROM AUTHOR]

Unconventional T cells (UTCs) are a heterogeneous group of T cells that typically exhibit rapid responses toward specific antigens from pathogens. Chronic hepatitis C virus (HCV) infection causes dysfunction of several subsets of UTCs. This altered phenotype and function of UTCs can persist over time even after direct‐acting antiviral (DAA)‐mediated clearance of chronic HCV. However, it is less clear if and how UTCs respond in acute, symptomatic HCV infection, a rare clinical condition, and if rapid DAA treatment of such patients reverses the caused perturbations within UTCs. Here, we comprehensively analyzed the phenotype and reinvigoration capacity of three major UTC populations, mucosal‐associated invariant T (MAIT) cells, γδ T cells, and CD4 and CD8 double‐negative αβ T cells (DNT cells) before, during, and after DAA‐mediated clearance of acute symptomatic HCV infection. Furthermore, MAIT cell functionality was systematically studied. We observed a reduced frequency of MAIT cells. However, remaining cells presented with a near‐to‐normal phenotype in acute infection, which contrasted with a significant dysfunction upon stimulation that was not restored after viral clearance. Notably, DNT and γδ T cells displayed a strong activation ex‐vivo in acute HCV infection, which subsequently normalized during the treatment. In addition, DNT cell activation was specifically associated with liver inflammation and inflammatory cytokines. Altogether, these data provide evidence that UTCs respond in a cell type‐specific manner during symptomatic HCV infection. However, even if early treatment is initiated, long‐lasting imprints within UTCs remain over time. [ABSTRACT FROM AUTHOR]

Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa-associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT cell compartment in COVID-19 patients with moderate and severe disease, as well as in convalescence. We show profound and preferential decline in MAIT cells in the circulation of patients with active disease paired with strong activation. Furthermore, transcriptomic analyses indicated significant MAIT cell enrichment and pro-inflammatory IL-17A bias in the airways. Unsupervised analysis identified MAIT cell CD69high and CXCR3low immunotypes associated with poor clinical outcome. MAIT cell levels normalized in the convalescent phase, consistent with dynamic recruitment to the tissues and later release back into the circulation when disease is resolved. These findings indicate that MAIT cells are engaged in the immune response against SARS-CoV-2 and suggest their possible involvement in COVID-19 immunopathogenesis. [ABSTRACT FROM AUTHOR]

Activated NK cells in severe COVID-19: Natural killer (NK) cells are cytotoxic lymphocytes that provide innate immune defense against viral infections and cancer, but little is known about their involvement in the host response to COVID-19. Maucourant et al. used high-dimensional flow cytometry to characterize NK cells in patients with moderate or severe COVID-19. SARS-CoV-2 infection was associated with fewer blood NK cells but a higher activation state in circulating NK cells. Severe COVID-19 resulted in an increase in "armed" NK cells containing high levels of cytotoxic proteins such as perforin. The adaptive NK subset was markedly expanded in a subset of severe patients. These findings lay the groundwork for future studies examining the mechanisms of NK cell activation in COVID-19 and their potential roles in host protection and immunopathology. Understanding innate immune responses in coronavirus disease 2019 (COVID-19) is important to decipher mechanisms of host responses and interpret disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections but might also contribute to immunopathology. Using 28-color flow cytometry, we here reveal strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients. This pattern was mirrored in single-cell RNA sequencing signatures of NK cells in bronchoalveolar lavage from COVID-19 patients. Unsupervised high-dimensional analysis of peripheral blood NK cells furthermore identified distinct NK cell immunotypes that were linked to disease severity. Hallmarks of these immunotypes were high expression of perforin, NKG2C, and Ksp37, reflecting increased presence of adaptive NK cells in circulation of patients with severe disease. Last, arming of CD56bright NK cells was observed across COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This study provides a detailed map of the NK cell activation landscape in COVID-19 disease. [ABSTRACT FROM AUTHOR]

Neutrophils are the most abundant leukocytes in human blood and play a primary role in resistance against invading microorganisms and in the acute inflammatory response. However, their role in colitis and colitis-associated colorectal cancer is still under debate. This study aims to dissect the role of neutrophils in these pathologic contexts by using a rigorous genetic approach. Neutrophil-deficient mice (Csf3r-/- mice) were used in classic models of colitis and colitis-associated colorectal cancer and the role of neutrophils was assessed by histologic, cellular, and molecular analyses coupled with adoptive cell transfer. We also performed correlative analyses using human datasets. Csf3r-/- mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared with control Csf3r+/+ mice and adoptive transfer of neutrophils in Csf3r-/- mice reverted the phenotype. In colitis, Csf3r-/- mice showed increased bacterial invasion and a reduced number of healing ulcers in the colon, indicating a compromised regenerative capacity of epithelial cells. Neutrophils were essential for γδ T-cell polarization and IL22 production. In patients with ulcerative colitis, expression of CSF3R was positively correlated with IL22 and IL23 expression. Moreover, gene signatures associated with epithelial-cell development, proliferation, and antimicrobial response were enriched in CSF3Rhigh patients. Our data support a model where neutrophils mediate protection against intestinal inflammation and colitis-associated colorectal cancer by controlling the intestinal microbiota and driving the activation of an IL22-dependent tissue repair pathway., (©2024 The Authors; Published by the American Association for Cancer Research.)