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The biliary tract is a complex tubular organ system spanning from the liver to the duodenum. It is the site of numerous acute and chronic disorders, many of unknown origin, that are often associated with cancer development and for which there are limited treatment options. Cholangiocytes with proinflammatory capacities line the lumen and specialised types of immune cells reside in close proximity. Recent technological breakthroughs now permit spatiotemporal assessments of immune cells within distinct niches and have increased our understanding of immune cell tissue residency. In this review, a comprehensive overview of emerging knowledge on the immunobiology of the biliary tract system is provided, with a particular emphasis on the role of distinct immune cells in biliary disorders.

T cells are critical to providing protection from severe COVID-19. However, whether repeated SARS-CoV-2 vaccination post-infection fuels T cell exhaustion or reshapes functionality remains debated. Here, we sampled SARS-CoV-2 convalescent donors of different COVID-19 disease severity before and after subsequent mRNA vaccination to determine the functional consequences of hybrid immunity. Using combined single-cell protein and transcriptional analysis of T cells targeting different regions of the SARS-CoV-2 genome, we identified that spike-specific T cells increased in magnitude but, notably, also gained improved polyfunctional characteristics. In contrast, T cell responses targeting non-spike proteins diminished with time and functionally remained unchanged. Elevated IFN-γ expression was a common hallmark of CD4+ and CD8+ T cell responses in mRNA-vaccinated individuals after SARS-CoV-2 infection. These responses were founded on both pre-expanded and newly detected CD8+ T cell clones after vaccination. Elevated IFN-γ production and magnitude of SARS-CoV-2-specific CD4+ and CD8+ T cells were also found in patients with B cell abnormalities (chronic lymphocytic leukemia; CLL) after booster mRNA vaccination (four doses). Collectively, these data demonstrate limited signs of functional exhaustion and instead cumulative benefits of booster vaccination post-infection, increasing the quantity and quality of cell-mediated immunity.

Biobanks function as important repositories for biological samples collected in health care. As such, they play an important role in enabling important medical research over time. In response to the covid-19 outbreak in Stockholm, Sweden, a group of specialists in intensive care, infectious diseases, and clinical microbiology, as well as scientists with experience in immunology and viral diseases, rapidly gathered. The group discussed how to cope with the prevailing situation, both from a clinical and a research-oriented perspective. Among strategies decided was an attempt to rapidly organize a biological sample collection organized in a biobank for immediate but also long-term research purposes. Given the pandemic conditions with a new virus, the biobank project and associated immediate immunological research tasks turned out to be challenging. In the following months, many lessons were learned from the systematic collection of clinical samples and associated immunological research. Many insights were gained of value for future pandemic preparedness.

Infection with the hepatitis delta virus (HDV) causes the most severe form of viral hepatitis. 15-20 million people are chronically infected with HDV. Hepatitis delta is believed to be an immune-mediated disease however adaptive immune responses against HDV are hardly detectable. This suggests a possible role of natural killer (NK) cells in the pathogenesis of HDV infection. To study this, we collected blood samples from 34 patients with hepatitis delta, 16 out of which were sampled during antiviral treatment with pegylated interferon alpha (peg-IFNalpha). Expression levels of activation and inhibitory NK cell receptors and multi-functional NK cell responses were assessed using 15-color flow cytometry. HDV infected patients exhibited higher baseline frequencies of NK cells. Peg-IFNalpha treatment was associated with a redistribution of NK cell subsets with increased numbers of CD56bright NK cells whereas total and CD56dim NK cells decreased. During treatment the most mature CD56dim NK cell subsets disappeared from the periphery and the frequency of immature CD56dim NK cells increased. Furthermore, the treatment resulted in decreased multi-functional NK cell responses against K562 cells, with and without additional IFNα stimulation. Taken together, we show that HDV infection increases the amount of NK cells. Furthermore our data suggest a reshaping of the NK pool by IFNα during treatment resulting in a loss of mature cells and decreased functional responses.

Epistatic interactions between killer cell immunoglobulin-like receptors (KIRs) and their cognate HLA class I ligands have important implications for reproductive success, anti-viral immunity, susceptibility to autoimmune conditions and cancer, as well as for graft-versus-leukemia reactions in settings of allogeneic stem cell transplantation. Although CD8 T cells are known to acquire KIRs when maturing from naïve to terminally differentiated cells, little information is available about the constitution of KIR repertoires on human CD8 T cells. Here, we have performed a high-resolution analysis of KIR-expression on CD8 T cells. The results show that most CD8 T cells possess a restricted KIR expression-pattern, often dominated by a single activating or inhibitory KIR. Furthermore, the expression of KIR, and its modulation of CD8 T cell function, was independent of expression of self-HLA class I-ligands. Finally, despite similarities in the stochastic regulation of KIRs by the bi-directional proximal promoter, the specificity of inhibitory KIRs on CD8 T cells was often distinct from that of NK cells in the same individual. The results provide new insight into the formation of KIR repertoires on human T cells.

Little is known about the human fetal immune system, but it has for long been considered as immature and unresponsive. Here we have investigated the development and function of human fetal natural killer (NK) cells. Using advanced flow cytometry, the phenotype and function of fetal NK cells was examined. In contrast to the notion that the fetal immune system is immature, we found that human fetal NK cells differentiate as early as gestational week 15 in utero, evidenced by the presence of NK cells with decrease in CD94/NKG2A and increase in CD16 and KIR expression. NK cells with varying degrees of differentiation were found in the fetal lung, liver, spleen, lymph nodes and bone marrow. Moreover, we show that fetal NK cells are highly responsive to cytokine stimulation and are capable of killing target cells both via natural cytotoxicity and by antibody-dependent cellular cytotoxicity. Strikingly, and in contrast to the education of adult NK cells, we demonstrate that while education via CD94/NKG2A was established in fetal NK cells, both self- and non-self KIR expression rendered fetal NK cells hyporesponsive, thus potentially blunting the response to maternal allogeneic cells. Fetal NK cells were also found to be highly sensitive to TGF-β-mediated inhibition as compared to adult NK cells. Taken together, our data indicate a fundamental difference in the education and regulation of fetal compared to adult NK cells, which have implications for fetal-maternal tolerance in utero.

Rodent-borne hantaviruses, such as Andes virus (ANDV) and Hantaan virus (HTNV) cause hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) respectively, two human diseases with high case-fatality rates and no specific treatment. Patients suffering from HPS or HFRS exhibit massive lymphocyte activation, including high numbers of responding CD8 T cells and NK cells, leading to hyperinflammation and vascular leakage. Interestingly, while endothelial cells are the main targets of hantaviruses, no direct cytopathic effects of the virus on the vascular endothelium have been found. Here, using an in vitro infection model with primary human endothelial cells, we show that hantavirus renders infected endothelial cells resistant to NK cell cytotoxicity by two mechanisms: first, by decreasing NK cell degranulation in an HLA class I-dependent manner and second, downstream of cytotoxic granule-release, by specifically inhibiting granzyme B and caspase 3 activity in infected endothelial cells. Although resistant to NK cell cytotoxicity, infected cells promote an highly activated NK cell phenotype and increased functional capacity. As clinical symptoms in HPS/HFRS most likely stem from the massive immune activation, a more complete understanding of how NK cell activation occurs and the role these activated cells may play in the pathogenesis of disease will be crucial to improve the clinical outcome of these, often fatal, infections.