Petter Höglund

Natural killer cell education in mice with single or multiple major histocompatibility complex class I molecules

The ability of murine NK cells to reject cells lacking self MHC class I expression results from an in vivo education process. To study the impact of individual MHC class I alleles on this process, we generated mice expressing single MHC class I alleles (Kb, Db, Dd, or Ld) or combinations of two or more alleles. All single MHC class I mice rejected MHC class I–deficient cells in an NK cell–dependent way. Expression of Kb or Dd conveyed strong rejection of MHC class I–deficient cells, whereas the expression of Db or Ld resulted in weaker responses. The educating impact of weak ligands (Db and Ld) was further attenuated by the introduction of additional MHC class I alleles, whereas strong ligands (Kb and Dd) maintained their educating impact under such conditions. An analysis of activating and inhibitory receptors in single MHC class I mice suggested that the educating impact of a given MHC class I molecule was controlled both by the number of NK cells affected and by the strength of each MHC class I–Ly49 receptor interaction, indicating that NK cell education may be regulated by a combination of qualitative and quantitative events.

Natural Killer Cell Inhibitory Receptor Expression in Humans and Mice: A Closer Look

The Natural Killer (NK) cell population is composed of subsets of varying sizes expressing different combinations of inhibitory receptors for MHC class I molecules. Genes within the NK gene complex, including the inhibitory receptors themselves, seem to be the primary intrinsic regulators of inhibitory receptor expression, but the MHC class I background is an additional Modulating factor. In this paper, we have performed a parallel study of the inhibitory receptor repertoire in inbred mice of the C57Bl/6 background and in a cohort of 44 humans. Deviations of subset frequencies from the “product rule (PR),” i.e., differences between observed and expected frequencies of NK cells, were used to identify MHC-independent and MHC-dependent control of receptor expression frequencies. Some deviations from the PR were similar in mice and humans, such as the decreased presence of NK cell subset lacking inhibitory receptors. Others were different, including a role for NKG2A in determining over- or under-representation of specific subsets in humans but not in mice. Thus, while human and murine inhibitory receptor repertoires differed in details, there may also be shared principles governing NK cell repertoire formation in these two species.

How we diagnose and treat neutropenia in adults

ABSTRACT Neutropenias (NPs), being acute and often transient, or chronic, range from life-threatening conditions with very low absolute neutrophil blood counts (ANC) to disorders characterized by only mild NP and of no obvious significance for health. Many are caused by genetic variations/mutations, e.g. the benign familial NP and the chronic severe NPs (e.g. Kostmann disease). Some of the latter are associated with various bodily malformations. Many of the mild-to-moderate NPs are signs of underlying disorders that need specialized treatments (e.g. HIV, hepatitis, autoimmune disorders, the large granular lymphocyte syndrome). We provide here means for the evaluation of a previously unknown NP, suggest a triage and treatments.

TLR stimulated eosinophils mediate recruitment and activation of NK cells in vivo

Eosinophils like many myeloid innate immune cells can provide cytokines and chemokines for the activation of other immune cells upon TLR stimulation. When TLR‐stimulated eosinophils were inoculated i.p. into wild‐type mice, and NK cells were rapidly recruited and exhibited antitumour cytotoxicity. However, when mice depleted of CD11c+ cells were used, a marked decrease in the number of recruited NK cells was observed. We postulated that CpG or LPS from the injected eosinophils could be transferred to host cells, which in turn could recruit NK cells. However, by inoculating mice deficient in TLR4 or TLR9 with LPS or CpG‐stimulated eosinophils respectively, NK cell recruitment was still observed alongside cytotoxicity and IFNγ production. CpG stimulation of eosinophils produced the pro‐inflammatory cytokine IL‐12 and the chemokine CXCL10, which are important for NK cell activation and recruitment in vivo. To demonstrate the importance of CXCL10 in NK cell recruitment, we found that CpG‐stimulated eosinophils pretreated with the gut microbial metabolite butyrate had reduced expression and production of CXCL10 and IL‐12 and concomitantly were poor at recruitment of NK cells and inducing IFNγ in NK cells. Therefore, eosinophils like other innate immune cells of myeloid origin can conceivably stimulate NK cell activity. In addition, products of the gut microbiota can be potential inhibitors of NK cell.

Sensitive detection of platelet-specific antibodies with a modified MAIPA using biotinylated antibodies and streptavidin-coated beads.

We have developed a modified monoclonal antibody immobilization of platelet antigens assay (MAIPA) with enhanced sensitivity in detecting antibodies against human platelet antigens (HPA), using biotinylated monoclonal antibodies, streptavidin-coated beads and detection by flow cytometry. The beads-MAIPA gave superior signal-to-noise resolution (>10-fold higher) for detection of anti-HPA-1a and anti-HPA-5b compared with the in-house standard MAIPA. Also, efficient and reproducible detection of anti-HPA-15 (CD109) was shown. The enhanced sensitivity was confirmed using WHO International Reference Reagents for anti-HPA-1a, anti-HPA-3a and anti-HPA-5b, which allowed comparison of detection endpoints with other laboratories. Finally, the beads-MAIPA was validated for quantification of anti-HPA-1a. The lower limit of quantification was 0.4IU/mL for beads-MAIPA, compared to 1IU/mL previously reported for standard MAIPA. Based on improved performance against all HPA-antibodies tested, the beads-MAIPA has replaced the standard MAIPA in our laboratory in diagnostics of conditions due to HPA-immunization, such as fetal and neonatal alloimmune thrombocytopenia (FNAIT).

Dear readers of the Scandinavian Journal of Immunology and ECI 2018 attendees

The Scandinavian Journal of Immunology has established itself over the last 45 years as one of the leading journals in the immunology field, through the publication of high‐ quality original research papers and reviews reflecting the developments in our discipline. The total circulation of the journal is now over 15 000. Nearly 7 700 institutions in the developing world also enjoy free or very low rate paid access to Scandinavian Journal of Immunology through various philanthropic initiatives (INTAS, INASP, Research4Life [HINARI‐WHO], AGORA). Since 2015, the Scandinavian Journal of Immunology is an online‐only journal and 325 308 article downloads were noted in 2017. The journals top users in 2017 reflect its international appeal and we are pleased that 1 280 researchers subscribe to our e‐toc alert service, through which tables of contents are sent direct to their Inbox. All papers for Scandinavian Journal of Immunology are submitted and refereed online, which secures rapid reviewing. The journal operates a stringent peer review process, which is a key aspect of all scientific publishing. All referees are given feedback on the decisions made on the papers they have reviewed. The average handling time for a paper is 20 days from submission to first decision and 48 days from submission to final decision. In 2017, the authors final accepted version was made available online within an average of 5 days from receipt at the production office. Thus, articles from the Scandinavian Journal of Immunology are downloadable and citable faster than ever. There are no page charges or submission fees for authors publishing in the journal. Reviews are freely accessible and because all publication is online, colour reproduction is free. Author‐funded open access is available for those whose funding bodies mandate publication in an open access journal. Members of immunological societies can receive the journal at the privileged rate of £30. This year, we have also seen a further increase in Scandinavian Journal of Immunologys impact factor—it has now reached 2.314—giving us confidence that the journal is moving in the right direction. I want to take this opportunity to thank the former Editor‐in‐Chief, Professor Roland Jonsson, his associated editors and editorial board and our journal administrator Kate Frøland, for all dedicated work. Because of them, the journal is in a very good shape to meet future challenges. Like many other journals, the Scandinavian Journal of Immunology must adapt to a changing publishing landscape. Electronic manuscript handling and printing have made it easier to launch new journals, and existing well‐ established journals expand their arena by creating chains of connected magazines to keep submissions “in the family”. Competition for high‐quality immunology submissions therefore tightens, making it important for the Scandinavian Journal of Immunology to adhere even more to its profile to keep its place among immunology journals. The Scandinavian Journal of Immunology has an established niche as the official journal of the Scandinavian Society for Immunology, and an important future goal is to increase submissions from Scandinavian researchers. However, we also receive many high‐quality submissions from several countries outside Scandinavia, not the least from Asia, and maintaining and increasing a steady flow of manuscripts from these countries is another important task. As a new Editor‐in‐Chief for the Scandinavian Journal of Immunology, I am dedicated to follow the successful path laid out by my predecessor to maintain and develop the Journal to remain a leading player in its sector. A strategic plan for the coming 5 years has been decided and myself, my deputy Editors‐in‐Chief and my group of Associate Editors are convinced that working towards a number of specific goals with clear and measurable follow‐up actions will further strengthen our journal. With published contributions from corresponding authors in 46 countries around the world, the Scandinavian Journal of Immunology is truly international in outlook. It is with great pleasure that we present the ECI2018 issue of the journal. It contains two discussion forum articles on the concept of immune tolerance, two reviews and four regular articles,5‐8 which together reflect the scope and the international profile of the Journal. I hope that you will enjoy these papers and that you will continue to follow us and, above all, submit your future papers to the Scandinavian Journal of Immunology.

Ethnic benign neutropenia: A phenomenon finds an explanation

Ethnic benign neutropenia (ENP) is the most common form of neutropenia (NP) worldwide, if an absolute blood neutrophil count (ANC) of < 1.5 G/L is used as definition. In 2009, ENP was associated with a gene variation in the ACKR1/DARC gene, the same variation that also confers the Duffy‐null trait. In 2017, a novel mechanism for ENP was introduced, questioning if ENP is a true neutropenic state, when the bodys total neutrophil count (TBNC) is concerned. Here, we summarize the current knowledge of ENP, asking (1) How well does the peripheral blood ANC predict the TBNC? (2) Can we improve methods for assessing TBNC? (3) Will estimates of TBNC predict infection propensity and reduce the need for further, costly workup?

Chapter Four – Natural killer cells in cancer

Publisher Summary nIntegrated with other immune cells, natural killer (NK) cells contribute to host anti-microbial and anti- tumor immunity. The provision of early defence mechanisms against viral infections, particularly herpes viruses, is perhaps the most important clinical effect by NK cells, but it was their cytotoxic potency against tumor cells that brought about their discovery. Their ability to lyse tumor cells in vitro without the requirement of prior immune sensitization of the host also gave them their name. NK cells are now well characterized with respect to their origin, differentiation, receptor repertoire, and effector functions properties. NK cells mediate killing of many different types of murine and human tumor cell lines in vitro. Several experimental studies in mice have also shown a role for NK cells in rejection responses against grafted murine tumor cell lines and against experimentally induced and spontaneously developing tumor in mice. Like cytotoxic T cells, NK cells possess different effector functions by which they mount anti- tumor responses. Two major mechanisms are used to induce target cell apoptosis, granule exocytosis and death receptor stimulation. NK cells can also produce many different cytokines as well as chemokines, some of which have a direct effect on tumor. The best studied cytokine in this respect is IFN-γ, a cytokine which decreases proliferation, enhances autophagy, limits metabolic activity of tumor cells and inhibits angiogenesis. IFN-γ produced by NK cells might also play a role in the regulation of killing by death receptors, either by downregulating anti-apoptotic proteins, or by upregulating caspases that are essential for death receptor-mediated apoptosis.