Tissue-specific nonheritable influences drive endometrial immune system variation.

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.

Type I Interferon Autoantibodies Correlate With Cellular Immune Alterations in Severe COVID-19.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe disease with increased morbidity and mortality among certain risk groups. The presence of autoantibodies against type I interferons (aIFN-Abs) is one mechanism that contributes to severe coronavirus disease 2019 (COVID-19). METHODS: This study aimed to investigate the presence of aIFN-Abs in relation to the soluble proteome, circulating immune cell numbers, and cellular phenotypes, as well as development of adaptive immunity. RESULTS: aIFN-Abs were more prevalent in critical compared to severe COVID-19 but largely absent in the other viral and bacterial infections studied here. The antibody and T-cell response to SARS-CoV-2 remained largely unaffected by the presence aIFN-Abs. Similarly, the inflammatory response in COVID-19 was comparable in individuals with and without aIFN-Abs. Instead, presence of aIFN-Abs had an impact on cellular immune system composition and skewing of cellular immune pathways. CONCLUSIONS: Our data suggest that aIFN-Abs do not significantly influence development of adaptive immunity but covary with alterations in immune cell numbers.

NK cells in COVID-19-from disease to vaccination.

Natural killer cells participate in the host innate immune response to viral infection. Conversely, natural killer cell dysfunction and hyperactivation can contribute to tissue damage and immunopathology. Here, we review recent studies with respect to natural killer cell activity during infection with SARS-CoV-2. Discussed are initial reports of patients hospitalized with COVID-19, which revealed prompt natural killer cell activation during the acute disease state. Another hallmark of COVID-19, early on observed, was a decrease in numbers of natural killer cells in the circulation. Data from patients with acute SARS-CoV-2 infection as well as from in vitro models demonstrated strong anti-SARS-CoV-2 activity by natural killer cells, likely through direct cytotoxicity as well as indirectly by secreting cytokines. Additionally, we describe the molecular mechanisms underlying natural killer cell recognition of SARS-CoV-2-infected cells, which involve triggering of multiple activating receptors, including NKG2D, as well as loss of inhibition through NKG2A. Discussed is also the ability of natural killer cells to respond to SARS-CoV-2 infection via antibody-dependent cellular cytotoxicity. With respect to natural killer cells in the pathogenesis of COVID-19, we review studies demonstrating how hyperactivation and misdirected NK cell responses could contribute to disease course. Finally, while knowledge is still rather limited, we discuss current insights suggesting a contribution of an early natural killer cell activation response in the generation of immunity against SARS-CoV-2 following vaccination with anti-SARS-CoV-2 mRNA vaccines.

Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy.

Immune cell differentiation is critical for adequate tissue-specific immune responses to occur. Here, we studied differentiation of human uterine natural killer cells (uNK cells). These cells reside in a tissue undergoing constant regeneration and represent the major leukocyte population at the maternal-fetal interface. However, their physiological response during the menstrual cycle and in pregnancy remains elusive. By surface proteome and transcriptome analysis as well as using humanized mice, we identify a differentiation pathway of uNK cells in vitro and in vivo with sequential acquisition of killer cell immunoglobulin-like receptors and CD39. uNK cell differentiation occurred continuously in response to the endometrial regeneration and was driven by interleukin-15. Differentiated uNK cells displayed reduced proliferative capacity and immunomodulatory function including enhanced angiogenic capacity. By studying human uterus transplantation and monozygotic twins, we found that the uNK cell niche could be replenished from circulation and that it was under genetic control. Together, our study uncovers a continuous differentiation pathway of human NK cells in the uterus that is coupled to profound functional changes in response to local tissue regeneration and pregnancy.

Human endometrial MAIT cells are transiently tissue resident and respond to Neisseria gonorrhoeae.

Mucosa-associated invariant T (MAIT) cells are non-classical T cells important in the mucosal defense against microbes. Despite an increasing interest in the immunobiology of the endometrial mucosa, little is known regarding human MAIT cells in this compartment. The potential role of MAIT cells as a tissue-resident local defense against microbes in the endometrium is largely unexplored. Here, we performed a high-dimensional flow cytometry characterization of MAIT cells in endometrium from pre- and postmenopausal women, and in decidua from first-trimester pregnancies. Furthermore, we assessed MAIT cell function by stimulation with Neisseria gonorrhoeae (N. gonorrhoeae). Endometrial MAIT (eMAIT) cells represented a stable endometrial immune cell population as limited dynamic changes were observed during the menstrual cycle, post menopause, or in response to pregnancy. Furthermore, eMAIT cells exhibited an activated tissue-resident phenotype. Despite expressing CD69 and CD103, eMAIT cells were replenished over time by circulating MAIT cells, as assessed using human uterus transplantation as a model. Finally, functional experiments revealed the capability of MAIT cells to respond to the sexually transmitted and tissue-relevant pathogen, N. gonorrhoeae. In conclusion, our study provides novel insight into human MAIT cell dynamics and anti-microbial properties in the human uterus.

Methods for High-Dimensional Flow Cytometry Analysis of Human MAIT Cells in Tissues and Peripheral Blood.

Mucosal-associated invariant T (MAIT) cells can be found throughout the human body, in peripheral blood, at mucosal sites, and, among other organs, in the liver. As unconventional T cells, MAIT cells have the capacity to readily respond to bacterial infections and are also engaged during anti-viral responses. To thoroughly investigate the MAIT cell phenotype and function in such conditions, multi-color flow cytometry is an appropriate and powerful tool. Yet, the recent rapid technological development within this methodology, with generation of highly complex data, has increased the need for downstream dimensionality reducing methods to fully interpret obtained results. Among such methods, stochastic neighbor embedding (SNE) analysis stands out as it provides intuitive low-dimensional representations of complex data. Here, we describe techniques and workflow for high-dimensional state-of-the-art investigation and analysis of human MAIT cells from blood and peripheral tissues.

The HLA-DQß1 insertion is a strong achalasia risk factor and displays a geospatial north-south gradient among Europeans.

Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQß1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQß1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P=1.84 × 10(-04), Sweden P=7.44 × 10(-05)). Combining all five European data sets - Central Europe, Italy, Spain, Poland and Sweden - the insertion is achalasia associated with Pcombined=1.67 × 10(-35). In addition, we observe that the frequency of the insertion shows a geospatial north-south gradient. The insertion is less common in northern (around 6-7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.