Human innate lymphocytes in host defense, tissue function and reproduction

The immune system is present in all tissues of the human body. In order to respond appropriately to infections, cells of the innate and adaptive immune system work in concert. In this thesis, we focused on natural killer cells (NK cells) and mucosa associated invariant T cells (MAIT cells), that are both present in peripheral blood and enriched in certain tissues such as the liver and, in case of NK cells, also the uterus where they are thought to be important regulators at the maternal-fetal interface. NK cells are able to react readily towards, among other things, virus-infected cells whereas MAIT cells are triggered by both cytokines in viral infections and bacterial metabolites during bacterial infections.

Hepatitis C virus (HCV) is a major cause of chronic viral hepatitis and is known to impact the immune system at several instances in order to establish chronic infection. Yet, with recent advances in anti-viral treatment, the infection can now be cured in a short period of time. As a result of this, it is possible to study the impact of HCV on the immune system in a dynamic setting. Therefore we investigated both NK cells and MAIT cells in HCV before, during, and after viral clearance of the infection. Despite rapid clearance of virus, imprints inflicted by chronic HCV infection remained within NK cells and MAIT cells over time. More specifically, MAIT cells were dysfunctional, present at a reduced frequency, and displayed an altered phenotype that was only partially restored upon infection clearance. Along similar lines, also the NK cell phenotype and the diversity of the NK cell compartment remained altered after rapid HCV viral clearance. We observed persistently reduced intraindividual diversity of NK cells after elimination of chronic HCV, whereas the interindividual diversity, more linked to liver damage, was restored over time.

Next, we studied peritoneal MAIT cells in ascites of patients with liver cirrhosis on the basis of viral hepatitis and other causes, and in the context of spontaneous bacterial peritonitis (SBP), a frequent and severe complication occurring in these patients. First, we could recapitulate the loss of MAIT cells in peripheral blood of cirrhosis patients in line with previous studies. Of note, in ascites, MAIT cells were more frequent than in blood and displayed a tissue-residency phenotype with increased functionality as compared to peripheral blood MAIT cells. Strikingly, during SBP, MAIT cells were the most recruited immune cells to the peritoneal cavity. Lastly, we investigated uterine NK cells (uNK cells) and hypothesized that these cells underwent a stepwise differentiation in response to endometrial regeneration and pregnancy. We present a model where uNK cells continuously differentiate throughout the menstrual cycle. This differentiation was associated with a functional shift towards immunomodulation and enhanced angiogenic function, possibly to aid in spiral artery formation during pregnancy.

In conclusion, we present data suggesting that chronic infections can leave a long-lasting imprint on the immune system. We further demonstrate that immune cell frequency, phenotype, and function can be altered depending on the respective tissue the cells reside in. This work increases our understanding of how innate lymphocytes respond to environmental cues, such as acute or chronic viral and bacterial challenges, as well as to normal physiological processes of the human body.

List of scientific papers

I. Julia Hengst*, Benedikt Strunz*, Katja Deterding, Hans-Gustaf Ljunggren, Edwin Leeansyah, Michael P. Manns Markus Cornberg, Johan K. Sandberg, Heiner Wedemeyer* and Niklas K. Björkström*. Nonreversible MAIT cell-dysfunction in chronic hepatitis C virus infection despite successful interferon-free therapy. European Journal of Immunology. 2016, vol. 46 (9), pp. 2204-22010. *Contributed equally.
https://doi.org/10.1002/eji.201646447

II. Benedikt Strunz*, Julia Hengst*, Katja Deterding, Michael P. Manns, Markus Cornberg, Hans-Gustaf Ljunggren, Heiner Wedemeyer* & Niklas K. Björkström*. Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity. Nature Communications. 2018, vol. 9 (1), pp. 2275-12. *Contributed equally.
https://doi.org/10.1038/s41467-018-04685-9

III. Christian E. Niehaus*, Benedikt Strunz*, Martin Cornillet, Christine S. Falk, Ansgar Schnieders, Benjamin Maasoumy, Svenja Hardtke, Michael P. Manns, Anke R.M. Kraft*, Niklas K. Björkström*, Markus Cornberg*. MAIT cells are enriched and highly functional in ascites of patients with decompensated liver cirrhosis. Hepatology. 2020, vol. 72 (4), pp. 1378-1393. *Contributed equally.
https://doi.org/10.1002/hep.31153

IV. Benedikt Strunz, Jonna Bister, Russell S. Hamilton, Hanna Jönsson, Ylva Crona-Guterstam, Egle Kvedaraite, Iva Filipovic, Natalie Sleiers, Bogdan Dumitrescu, Danielle Friberg, Mats Brännström, Antonio Lentini, Björn Reinius, Martin Cornillet, Tim Willinger, Sebastian Gidlöf, Martin A. Ivarsson, and Niklas K. Björkström. Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy. [Manuscript]