The ontogeny and regulation of human natural killer cells

Natural Killer (NK) cells are members of the innate lymphoid cell (ILC) family and take part in the detection and eradication of virus-infected and transformed cells. In this thesis, together with my colleagues I have investigated how NK cells and other ILCs develop and function during human fetal development, how NK cells are functionally regulated (educated) via the activating receptor KIR2DS1, and how NK cells in our body are affected during the early phase of an acute viral infection. Little is known about the ontogeny of NK cells and other ILCs in fetal development. The characterization of ILCs has been hampered by their overlapping surface phenotypes. In contrast, ILC transcription factor expression is more specific, and by combining multicolor flow cytometry analysis of transcription factors and surface markers expressed by different fetal ILC subsets, we were able to study and model their development and differentiation. All ILC subsets were detected as early as gestational week six, and their distribution varied depending on both tissue and gestational age. Moreover, putative precursors of NK cells were identified as cells that sequentially lost CD34 and acquired CD122, Eomes, CD94/NKG2A, T-bet, and CD16. In addition putative CD34+ progenitors of RORγt+ ILCs were identified. In the second trimester of fetal development, analysis of mature fetal NK cell subsets revealed that stage 4 and stage 5 NK cells differed in frequency in fetal organs, and the highest NK cell frequency was found in the fetal liver and lung. The vast majority of fetal NK cells were NKG2A+, and fetal lung NK cells also frequently expressed killercell immunoglobulin-like receptors (KIR). Interestingly, while NKG2A educated fetal NK cells similar to adult NK cells, KIR expression on fetal NK cells was linked to hyporesponsiveness, thus contrasting education of NK cells after birth. Nevertheless, fetal NK cells were highly responsive to cytokines, as well as to antibody-coated target cells, suggesting they may take part in fetal immune responses against in utero infections, while remaining tolerant to maternal cells crossing the placenta. While it is established that NK cells in adults are educated via inhibitory KIRs, it is not known how activating KIRs such as KIR2DS1 affects NK cells. By combining antibodies against four inhibitory KIRs, NKG2A, and KIR2DS1, we were able to interrogate the regulation of NK cells by KIR2DS1. We found that KIR2DS1 singlepositive NK cells exist in vivo, and that the presence of the ligand for KIR2DS1, HLAC2, resulted in hyporesponsiveness of such NK cells, thus ensuring self-tolerance. Our findings represent the first identification of NK cell education via activating KIR. The human NK cell response to viral infections is not well understood. To this end we employed the live attenuated yellow fever vaccine 17D as an in vivo model of an acute viral infection. Our results show that the vaccine primed NK cells, and that less differentiated CD57- NK cells dominated the response, which peaked at day 6-10 post vaccination. Moreover, KIR expression on NK cells did not affect their response to the vaccine, indicating that NK cells expressing self-KIR and non-self KIR contributed equally to the NK cell response to the vaccination

Hyperparathyroidism and new onset diabetes after renal transplantation.

Secondary hyperparathyroidism persists after renal transplantation in a substantial number of patients. Primary hyperparathyroidism and secondary hyperparathyroidism are both associated with abnormalities in glucose metabolism, such as insufficient insulin release and glucose intolerance. The association of hyperparathyroidism and diabetes after renal transplantation has, as far as we know, not been studied. Our aim was to investigate whether hyperparathyroidism is associated with new-onset diabetes mellitus after transplantation (NODAT) during the first year posttransplantation

Identity leadership and cohesion in elite sport: The mediating role of intra-team communication

One perspective on leadership that has recently gained increased attention in sport is identity leadership; however, research on elite sport teams is still in its infancy. Thus, the main purpose of this research is to investigate identity leadership in elite team sports in relation to task cohesion, and subsequently to explore the mediating role of the intra-team communication dimensions of acceptance and distinctiveness. A cross-sectional design was employed and 441 elite athletes from division 1 and division 2 in handball and ice hockey participated in the present study. Structural equation modeling was used to assess relationships between identity leadership and task cohesion, and the mediating role of acceptance and distinctiveness. Results revealed that identity leadership positively predicted task cohesion, and that this relationship was mediated by intrateam communication acceptance. In conclusion, findings in the present study expand our understanding of performance-related benefits of identity leadership in elite sport.Identity leadership and cohesion in elite sport: The mediating role of intra-team communicationpublishedVersio

The Role of the Results of Functional Tests and Psychological Factors on Prediction of Injuries in Adolescent Female Football Players

Football is a popular sport among adolescent females. Given the rate of injuries in female footballers, identifying factors that can predict injuries are important. These injuries are often caused by complex reasons. The aim of this study was to investigate if the combination of demographic (age, number of training and match play hours/week), psychosocial (perceived stress, adaptive coping strategies) and physiological factors (functional performance) can predict a traumatic injury in adolescent female footballers. A cohort consisting of 419 female football players aged 13–16 years was established. Baseline questionnaires covered potential risk factors for sport injuries, and measurements included football-related functional performance tests. Data were collected prospectively with a weekly online questionnaire for 52 weeks covering, e.g., injuries, training, and match play hours/week. A total of 62% of the players reported at least one traumatic injury during the 52 weeks. The coping strategy “positive reframing” had the strongest association with the risk of traumatic injuries. The combination of more frequent use of the coping strategy, positive reframing, and high levels of physical performance capacity may prevent a traumatic injury in adolescent female footballers. Coaches are encouraged to adopt both physiological and psychological factors when preventing injuries in young female footballers.publishedVersio

Response-order effects in survey methods: A randomized controlled crossover study in the context of sport injury prevention

Consistency tendency is characterized by the propensity for participants responding to subsequent items in a survey consistent with their responses to previous items. This method effect might contaminate the results of sport psychology surveys using cross-sectional design. We present a randomized controlled crossover study examining the effect of consistency tendency on the motivational pathway (i.e., autonomy support → autonomous motivation → intention) of self-determination theory in the context of sport injury prevention. Athletes from Sweden (N = 341) responded to the survey printed in either low interitem distance (IID; consistency tendency likely) or high IID (consistency tendency suppressed) on two separate occasions, with a one-week interim period. Participants were randomly allocated into two groups, and they received the survey of different IID at each occasion. Bayesian structural equation modeling showed that low IID condition had stronger parameter estimates than high IID condition, but the differences were not statistically significant

Dubiofossils from a Mars-analogue subsurface palaeoenvironment: the limits of biogenicity criteria

ACKNOWLEDGMENTS S. M. acknowledges funding by the European Union's Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie grant agreement 747877. MI acknowledges funding from Swedish Research Council (Contract 2017-04129) and funding from the Paul Scherrer Institute, Villigen, Switzerland (20130185, 20141047) granted to Stefan Bengtson. DW acknowledges funding from the Australian Research Council via a Future Fellowship (FT140100321). The authors acknowledge the facilities, and the scientific and technical assistance of Microscopy Australia at the Centre for Microscopy, Characterisation & Analysis, The University of Western Australia, a facility funded by the University, State and Commonwealth Governments. The chemical garden experiments were supported by the National Science Foundation under Grant No. 1609495 to O.S. Chemical garden SEM measurements were carried out at the Condensed Matter and Materials Physics User Facility of Florida State University. We thank Dr. Eric Lochner for sharing his technical expertise. We acknowledge the Paul Scherrer Institut, Villigen, Switzerland for provision of synchrotron radiation beamtime at the TOMCAT beamline X02DA of the Swiss Light Source and would like to thank Federica Marone for help at the beamline and SRXTM analyses. We thank three anonymous reviewers for their comments, which greatly improved the manuscript. Funding information Paul Scherrer Institut, Grant/Award Number: 20130185 and 20141047; Vetenskapsrådet, Grant/Award Number: 2017-04129; Australian Research Council, Grant/Award Number: FT140100321; H2020 Marie Skłodowska-Curie Actions, Grant/Award Number: 747877; National Science Foundation, Grant/Award Number: 1609495Peer reviewedPublisher PD

Validity of the Brief Child and Family Phone Interview by comparison with Longitudinal Expert All Data diagnoses in outpatients

Background: The Brief Child and Family Phone Interview (BCFPI) is a standardized intake and follow-up interview used in child and adolescent mental health services (CAMHS). Although it has shown good validity compared with other measures using parent reports, it has not yet been compared with diagnoses derived from a Longitudinal Expert All Data (LEAD) procedure, which includes information from separate diagnostic interviews with parent(s) and child. The aim was to compare the BCFPI evaluation in an outpatient child and adolescent psychiatry setting with an evaluation derived from a LEAD procedure.Methods: At four Swedish outpatient CAMHS, 267 patients were interviewed at intake with the BCFPI. Within six weeks, patients and parents were interviewed separately with the 2009 version of the semi-structured Kiddie Schedule for Affective Disorders and Schizophrenia for School-age Children, Present and Lifetime Version (K-SADS-PL) and parents completed the Child Behavior Checklist (CBCL). LEAD diagnoses were subsequently determined by two senior clinicians based on 1.2 years of clinical records including the K-SADS-PL and ensuing information from further assessments, psychological tests, information from teachers and other informants as well as treatment outcome. The Diagnostic and Statistical Manual of Mental Disorders subscales from the CBCL and the subscales from the BCFPI were compared with LEAD diagnoses. These measured symptoms of attention-deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, separation anxiety disorder, generalized anxiety disorder, and major depressive disorder.Results: The criterion validity for BCFPI versus LEAD diagnoses was fair for oppositional defiant disorder (area under curve, 0.73), generalized anxiety disorder (0.73) and major depressive disorder (0.78), good for attention-deficit hyperactivity disorder (0.81) and conduct disorder (0.83), and excellent for separation anxiety disorder (0.90). The screening properties of BCFPI and CBCL were similar.Conclusion: The BCFPI is a concise and valid tool, performed along with the larger and more established CBCL, in screening for major psychiatric disorders. It is well suited as an intake interview in CAMHS

Exceptional preservation of fungi as H2-bearing fluid inclusions in an Early Quaternary paleo-hydrothermal system at Cape Vani, Milos, Greece

The production of H2 in hydrothermal systems and subsurface settings is almost exclusively assumed a result of abiotic processes, particularly serpentinization of ultramafic rocks. The origin of H2 in environments not hosted in ultramafic rocks is, as a rule, unjustifiably linked to abiotic processes. Additionally, multiple microbiological processes among both prokaryotes and eukaryotes are known to involve H2-production, of which anaerobic fungi have been put forward as a potential source of H2 in subsurface environments, which is still unconfirmed. Here, we report fungal remains exceptionally preserved as fluid inclusions in hydrothermal quartz from feeder quartz-barite veins from the Cape Vani Fe-Ba-Mn ore on the Greek island of Milos. The inclusions possess filamentous or near-spheroidal morphologies interpreted as remains of fungal hyphae and spores, respectively. They were characterized by microthermometry, Raman spectroscopy, and staining of exposed inclusions with WGA-FITC under fluorescence microscopy. The spheroidal aqueous inclusions interpreted as fungal spores are unique by their coating of Mn-oxide birnessite, and gas phase H2. A biological origin of the H2 resulting from anaerobic fungal respiration is suggested. We propose that biologically produced H2 by micro-eukaryotes is an unrecognized source of H2 in hydrothermal systems that may support communities of H2-dependent prokaryote

Tissue-Specific Education of Decidual NK Cells.

During human pregnancy, fetal trophoblast cells invade the decidua and remodel maternal spiral arteries to establish adequate nutrition during gestation. Tissue NK cells in the decidua (dNK) express inhibitory NK receptors (iNKR) that recognize allogeneic HLA-C molecules on trophoblast. Where this results in excessive dNK inhibition, the risk of pre-eclampsia or growth restriction is increased. However, the role of maternal, self-HLA-C in regulating dNK responsiveness is unknown. We investigated how the expression and function of five iNKR in dNK is influenced by maternal HLA-C. In dNK isolated from women who have HLA-C alleles that carry a C2 epitope, there is decreased expression frequency of the cognate receptor, KIR2DL1. In contrast, women with HLA-C alleles bearing a C1 epitope have increased frequency of the corresponding receptor, KIR2DL3. Maternal HLA-C had no significant effect on KIR2DL1 or KIR2DL3 in peripheral blood NK cells (pbNK). This resulted in a very different KIR repertoire for dNK capable of binding C1 or C2 epitopes compared with pbNK. We also show that, although maternal KIR2DL1 binding to C2 epitope educates dNK cells to acquire functional competence, the effects of other iNKR on dNK responsiveness are quite different from those in pbNK. This provides a basis for understanding how dNK responses to allogeneic trophoblast affect the outcome of pregnancy. Our findings suggest that the mechanisms that determine the repertoire of iNKR and the effect of self-MHC on NK education may differ in tissue NK cells compared with pbNK.This work was supported by Wellcome Trust Grants 090108/Z/09/Z and 085992/Z/08/Z, as well as by British Heart Foundation Grant PG/09/077/27964. P.R.K. was the recipient of a Wellcome Trust Ph.D. studentship.This is the final version of the article. It first appeared from the American Association of Immunologists via http://dx.doi.org/10.4049/​jimmunol.150122