| 1. |
- Beziat, Vivien, et al.
(author)
-
NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs
- 2013
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 121:14, s. 2678-2688
-
Journal article (peer-reviewed)abstract
- Human natural killer (NK) cells are functionally regulated by killer cell immunoglobulin-like receptors (KIRs) and their interactions with HLA class I molecules. As KIR expression in a given NK cell is genetically hard-wired, we hypothesized that KIR repertoire perturbations reflect expansions of unique NK-cell subsets and may be used to trace adaptation of the NK-cell compartment to virus infections. By determining the human KIR-ome at a single-cell level in more than 200 donors, we were able to analyze the magnitude of NK cell adaptation to virus infections in healthy individuals. Strikingly, infection with human cytomegalovirus (CMV), but not with other common herpesviruses, induced expansion and differentiation of KIR-expressing NK cells, visible as stable imprints in the repertoire. Education by inhibitory KIRs promoted the clonal-like expansion of NK cells, causing a bias for self-specific inhibitory KIRs. Furthermore, our data revealed a unique contribution of activating KIRs (KIR2DS4, KIR2DS2, or KIR3DS1), in addition to NKG2C, in the expansion of human NK cells. These results provide new insight into the diversity of KIR repertoire and its adaptation to virus infection, suggesting a role for both activating and inhibitory KIRs in immunity to CMV infection.
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| 2. |
- Björkström, Niklas K, et al.
(author)
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Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus
- 2011
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 208:1, s. 13-21
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Journal article (peer-reviewed)abstract
- Natural killer (NK) cells are known to mount a rapid response to several virus infections. In experimental models of acute viral infection, this response has been characterized by prompt NK cell activation and expansion followed by rapid contraction. In contrast to experimental model systems, much less is known about NK cell responses to acute viral infections in humans. We demonstrate that NK cells can rapidly expand and persist at highly elevated levels for >60 d after human hantavirus infection. A large part of the expanding NK cells expressed the activating receptor NKG2C and were functional in terms of expressing a licensing inhibitory killer cell immunoglobulin-like receptor (KIR) and ability to respond to target cell stimulation. These results demonstrate that NK cells can expand and remain elevated in numbers for a prolonged period of time in humans after a virus infection. In time, this response extends far beyond what is considered normal for an innate immune response.
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| 3. |
- Blomberg, Hans, 1963-, et al.
(author)
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Impact of prehospital trauma life support (PHTLS) training of ambulance caregivers on the outcome of traffic injury victims – a nation-wide study.
-
Other publication (other academic/artistic)abstract
- Background: Prehospital trauma life support (PHTLS) is a widely implemented educational program for prehospital trauma care. Evidence for improved patient outcome is, however, limited. The primary aim of this nation-wide study was to investigate the association between regional implementation of PHTLS training and mortality after traffic injuries.Methods: We extracted from the Swedish National Patient Registry and the Cause of Death Registry information on victims of motor vehicle traffic injuries in Sweden from 2001 to 2004 (n=28 041). During this time period, PHTLS training was implemented at a varying pace in different regions. We used a Bayesian approach with Markov chain Monte Carlo to estimate odds ratios (OR) for prehospital and 30-day mortality. We entered region and hospital into hierarchical models and controlled for the calendar year for each injury. We analyzed the time to death and time to return to work using Cox’s proportional hazards frailty models.Results: A total of 1395 individuals died before being admitted to hospital. After multivariable adjustment, the OR for prehospital mortality with PHTLS-trained prehospital staff was 1.11 (95% credibility interval, 0.88 to 1.38). For 30-day mortality (365 deaths), the adjusted OR was 0.80 (95% credibility interval, 0.53 to 1.17). There was no association between PHTLS training and time to death (hazard ratio 0.99; 95% confidence interval, 0.85 to 1.14) or time to return to work (hazard ratio 0.98, 95% confidence interval, 0.92 to 1.05).Conclusion: The implementation of PHTLS training did not appear to reduce mortality or disability after motor vehicle traffic injuries. .
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| 4. |
- Blomberg, Hans, 1963-
(author)
-
Influence of The Education and Training of Prehospital Medical Crews on Measures of Performance and Patient Outcomes
- 2013
-
Doctoral thesis (other academic/artistic)abstract
- Prehospital care has developed dramatically the last decades with the implementation of new devices and educational concepts. Clinical decisions and treatments have moved out from the hospitals to the prehospital setting. In Sweden this has been accompanied by an increase in the level of competence, i.e. by introducing nurses in the ambulances. With some exceptions the scientific support for these changes is poor.This thesis deals with such changes in three different subsets of prehospital care: Cardiopulmonary resuscitation (CPR), the stroke chain of survival and trauma care.We assessed the performance of ambulance crews during CPR, using a mechanical compression device, as compared to CPR using manual compressions. There was a strikingly poor quality of compressions using the mechanical device compared to CPR with manual compressions. The result calls for caution when implementing a chest compression device in clinical practice and reinforce the importance of randomised controlled trials to evaluate new interventions. Careful attention should be given to the assurance of correct application of the device. Further implementation without evaluation of the quality of mechanical compressions in a clinical setting is discouraged.Among patients with a prehospital suspicion of stroke we analysed the ambulance nurses’ ability to select the correct patient subset eligible for a CT scan as a preparation for potential thrombolysis. The results do not support an implementation of a bypass of the emergency department, using ambulance nurse competence to select patients eligible and suitable for a CT scan without a preceding assessment by a physician.The association between the Prehospital Trauma Life Support (PHTLS) course and the outcome in victims of trauma was analysed in two observational studies. A study covering one county gave some support for a protective effect from PHTLS, but the estimate had a low precision. A nationwide study, covering all of Sweden, could not confirm those results. Although there was a reduction in mortality over time coinciding with the implementation of PHTLS, it did not appear to be associated with the implementation of PHTLS. Thus, we could not detect any clear beneficial impact of the PHTLS course on the outcome of trauma patients.
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| 5. |
- Blomberg, Hans, et al.
(author)
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Prehospital Trauma Life Support Training of Ambulance Caregivers and the Outcomes of Traffic-Injury Victims in Sweden
- 2013
-
In: Journal of the American College of Surgeons. - : Ovid Technologies (Wolters Kluwer Health). - 1072-7515 .- 1879-1190. ; 217:6, s. 1010-1019
-
Journal article (peer-reviewed)abstract
- BACKGROUND:There is limited evidence that the widely implemented Prehospital Trauma Life Support (PHTLS) educational program improves patient outcomes. The primary aim of this national study in Sweden was to investigate the association between regional implementation of PHTLS training and mortality after traffic injuries.STUDY DESIGN:We extracted information from the Swedish National Patient Registry and the Cause of Death Registry on victims of motor-vehicle traffic injuries in Sweden from 2001 to 2004 (N = 28,041). During this time period, PHTLS training was implemented at a varying pace in different regions. To control for other influences on patient outcomes related to regional and hospital-level effects, such as variations in performance of trauma care systems, we used Bayesian hierarchical regression models to estimate odds ratios for prehospital mortality and 30-day mortality after hospital admission. We also controlled for the calendar year for each injury to account for period effects. We analyzed the time to death after hospital admission and time to return to work using Cox's proportional hazards frailty models.RESULTS:After multivariable adjustment, the odds ratio for prehospital mortality with PHTLS-trained prehospital staff was 1.54 (95% credibility interval, 1.07-2.13). For 30-day mortality among those surviving to hospital admission, the odds ratio was 0.85 (95% credibility interval, 0.45-1.48). There was no association between PHTLS training and time to death (hazard ratio = 0.99; 95% CI, 0.85-1.14) or time to return to work (hazard ratio = 0.98; 95% CI, 0.92-1.05).CONCLUSIONS:In this observational study, the implementation of PHTLS training did not appear to be associated with reduced mortality or ability to return to work after motor-vehicle traffic injuries.
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| 6. |
- Buggert, Marcus, et al.
(author)
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T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection.
- 2014
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 10:7
-
Journal article (peer-reviewed)abstract
- CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation.
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| 7. |
- Engblom, Camilla, et al.
(author)
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Spatial transcriptomics of B cell and T cell receptors reveals lymphocyte clonal dynamics
- 2023
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 382:6675, s. 8486-
-
Journal article (peer-reviewed)abstract
- The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed spatial transcriptomics of variable, diversity, and joining (VDJ) sequences (Spatial VDJ), a method that maps B cell and T cell receptor sequences in human tissue sections. Spatial VDJ captures lymphocyte clones that match canonical B and T cell distributions and amplifies clonal sequences confirmed by orthogonal methods. We found spatial congruency between paired receptor chains, developed a computational framework to predict receptor pairs, and linked the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity and lineage trajectories within their anatomical niche. Thus, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, providing a platform to harness clonal sequences for therapy.
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| 8. |
- Evren, Elza, et al.
(author)
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Distinct developmental pathways from blood monocytes generate human lung macrophage diversity
- 2021
-
In: Immunity. - : Elsevier. - 1074-7613 .- 1097-4180. ; 51, s. 35-35
-
Journal article (peer-reviewed)abstract
- The study of human macrophages and their ontogeny is an important unresolved issue. Here, we use a humanized mouse model expressing human cytokines to dissect the development of lung macrophages from human hematopoiesis in vivo. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) generated three macrophage populations, occupying separate anatomical niches in the lung. Intravascular cell labeling, cell transplantation, and fate-mapping studies established that classical CD14+ blood monocytes derived from HSPCs migrated into lung tissue and gave rise to human interstitial and alveolar macrophages. In contrast, non-classical CD16+ blood monocytes preferentially generated macrophages resident in the lung vasculature (pulmonary intravascular macrophages). Finally, single-cell RNA sequencing defined intermediate differentiation stages in human lung macrophage development from blood monocytes. This study identifies distinct developmental pathways from circulating monocytes to lung macrophages and reveals how cellular origin contributes to human macrophage identity, diversity, and localization in vivo.
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| 9. |
- Forkel, Marianne, et al.
(author)
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Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers
- 2017
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In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 47:8, s. 1280-1294
-
Journal article (peer-reviewed)abstract
- Human innate lymphoid cells have been described to exist in different organs, with functional deregulation of these cells contributing to several disease states. Here, we performed the first detailed characterization of the phenotype, tissue-residency properties, and functionality of ILC1s, ILC2s, and ILC3s in the human adult and fetal liver. In addition, we investigated changes in the ILC compartment in liver fibrosis. A unique composition of tissue-resident ILCs was observed in nonfibrotic livers as compared with that in mucosal tissues, with NKp44− ILC3s accounting for the majority of total intrahepatic ILCs. The frequency of ILC2s, representing a small fraction of ILCs in nonfibrotic livers, increased in liver fibrosis and correlated directly with the severity of the disease. Notably, intrahepatic ILC2s secreted the profibrotic cytokine IL-13 when exposed to IL-33 and thymic stromal lymphopoetin (TSLP); these cytokines were produced by hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells in response to TLR-3 stimulation. In summary, the present results provide the first detailed characterization of intrahepatic ILCs in human adult and fetal liver. The results indicate a role for ILC2s in human liver fibrosis, implying that targeting ILC2s might be a novel therapeutic strategy for its treatment.
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| 10. |
- Forkel, Marianne, et al.
(author)
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Distinct Alterations in the Composition of Mucosal Innate Lymphoid Cells in Newly Diagnosed and Established Crohns Disease and Ulcerative Colitis
- 2019
-
In: Journal of Crohn's & Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 13:1, s. 67-78
-
Journal article (peer-reviewed)abstract
- Background and Aims: Innate lymphoid cells [ILC] have been suggested to play a role in inflammatory bowel disease [IBD]. Here, we investigated the ILC compartment in intestinal biopsies and blood from distinct patient groups with Crohns disease [CD] and ulcerative colitis [UC], either newly diagnosed or with disease established for at least 1 year. This approach allowed us to simultaneously investigate temporal, disease-specific, and tissue-specific changes in ILC composition in IBD. Methods: ILC subset frequencies, phenotype, and transcription factor profile in blood and intestinal biopsies were investigated by multi-parameter flow cytometry analysis. Endoscopic disease severity was judged using the ulcerative colitis endoscopic index of severity and the simple endoscopic score for Crohns disease. Results: The frequency of NKp44(+)ILC3 was decreased in inflamed tissue, both in patients with CD and those with UC, already at the time of diagnosis, and correlated with disease severity. Simultaneously, the frequency of ILC1 was increased in patients with CD, whereas the frequency of ILC2 was increased in patients with UC. However, in patients with established UC or CD, both ILC1 and ILC2 were increased. In contrast to the ILC composition in inflamed tissue, ILC in non-inflamed tissue or blood were unchanged compared with non-IBD controls. Finally, in patients undergoing treatment with an anti-alpha(4)beta(7) antibody the frequencies of ILC in peripheral blood remained unchanged. Conclusions: We report both shared and distinct changes in ILC composition depending on diagnosis and disease duration. The alterations in ILC composition in IBD occur selectively at inflamed sites in the gut.
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| 11. |
- Hard, Joanna, et al.
(author)
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Conbase : a software for unsupervised discovery of clonal somatic mutations in single cells through read phasing
- 2019
-
In: Genome Biology. - : BMC. - 1465-6906 .- 1474-760X. ; 20
-
Journal article (peer-reviewed)abstract
- Accurate variant calling and genotyping represent major limiting factors for downstream applications of single-cell genomics. Here, we report Conbase for the identification of somatic mutations in single-cell DNA sequencing data. Conbase leverages phased read data from multiple samples in a dataset to achieve increased confidence in somatic variant calls and genotype predictions. Comparing the performance of Conbase to three other methods, we find that Conbase performs best in terms of false discovery rate and specificity and provides superior robustness on simulated data, in vitro expanded fibroblasts and clonal lymphocyte populations isolated directly from a healthy human donor.
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| 12. |
- Hård, Joanna, et al.
(author)
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Long-read whole-genome analysis of human single cells
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
-
Journal article (peer-reviewed)abstract
- Long-read sequencing has dramatically increased our understanding of human genome variation. Here, we demonstrate that long-read technology can give new insights into the genomic architecture of individual cells. Clonally expanded CD8+ T-cells from a human donor were subjected to droplet-based multiple displacement amplification (dMDA) to generate long molecules with reduced bias. PacBio sequencing generated up to 40% genome coverage per single-cell, enabling detection of single nucleotide variants (SNVs), structural variants (SVs), and tandem repeats, also in regions inaccessible by short reads. 28 somatic SNVs were detected, including one case of mitochondrial heteroplasmy. 5473 high-confidence SVs/cell were discovered, a sixteen-fold increase compared to Illumina-based results from clonally related cells. Single-cell de novo assembly generated a genome size of up to 598 Mb and 1762 (12.8%) complete gene models. In summary, our work shows the promise of long-read sequencing toward characterization of the full spectrum of genetic variation in single cells.
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| 13. |
- Johansson, Jakob, et al.
(author)
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Prehospital Trauma Life Support (PHTLS) training of ambulance caregivers and impact on survival of trauma victims
- 2012
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In: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 83:10, s. 1259-1264
-
Journal article (peer-reviewed)abstract
- BACKGROUND:The Prehospital Trauma Life Support (PHTLS) course has been widely implemented and approximately half a million prehospital caregivers in over 50 countries have taken this course. Still, the effect on injury outcome remains to be established. The objective of this study was to investigate the association between PHTLS training of ambulance crew members and the mortality in trauma patients.METHODS:A population-based observational study of 2830 injured patients, who either died or were hospitalized for more than 24h, was performed during gradual implementation of PHTLS in Uppsala County in Sweden between 1998 and 2004. Prehospital patient records were linked to hospital-discharge records, cause-of-death records, and information on PHTLS training and the educational level of ambulance crews. The main outcome measure was death, on scene or in hospital.RESULTS:Adjusting for multiple potential confounders, PHTLS training appeared to be associated with a reduction in mortality, but the precision of this estimate was poor (odds ratio, 0.71; 95% confidence interval, 0.42-1.19). The mortality risk was 4.7% (36/763) without PHTLS training and 4.5% (94/2067) with PHTLS training. The predicted absolute risk reduction is estimated to correspond to 0.5 lives saved annually per 100,000 population with PHTLS fully implemented.CONCLUSIONS:PHTLS training of ambulance crew members may be associated with reduced mortality in trauma patients, but the precision in this estimate was low due to the overall low mortality. While there may be a relative risk reduction, the predicted absolute risk reduction in this population was low.
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| 14. |
- Michaëlsson, Jakob
(author)
-
Decoding NK cell receptor specificity : functional and structural studies of MHC class 1 subcomponents
- 2002
-
Doctoral thesis (other academic/artistic)abstract
- Natural Killer (NK) cells are an important part of the innate immune system. They can lyse target cells and secrete immunoregulatory cytokines early during immune responses. They mediate protection against viruses and tumours, and can reject MHC class I mismatched bone marrow grafts. NK cell function is regulated through activating and inhibitory receptors, many of which recognize MHC class I molecules on the surface of surrounding cells. The overall aim of this thesis has been to elucidate the MHC class I specificity of NK cell receptors. We have investigated the role of the heavy chain, the beta2m subunit and the peptide of MHC class I complexes in the interaction with NK cell receptors, primarily Ly49 receptors in the mouse and CD94/NKG2 receptors in the human. The MHC class I specificity of NK cell receptors was studied by direct visualisation using soluble, fluorescently labelled MHC class I tetramers, by X-ray crystallography and in functional assays. After having established the novel technique of soluble, fluorescently labelled tetrameric MHC class I molecules in our laboratory, we assessed the binding of such MHC class I tetramers (H-2D , 14- 2Kb and H-2D) to different Ly49 receptors. We could demonstrate that they bind in an allelespecific manner to Ly49 receptors and concluded that the MHC class I associated glycosylation was not required for the interaction between H-2Dd, H-2Db and Ly49A, nor for the interaction between H-2Kb, H-2Db and Ly49C. Furthermore we could show that the interaction between Ly49C and H-2Kb was peptide-selective, confirming and extending earlier functional data from our laboratory in a direct binding assay. Finally we identified H-2D b as a new ligand for both Ly49A and Ly49C. The role of the MHC class I bound beta2M subunit in recognition by Ly49 receptors was investigated using MHC class I tetramers of H-2Dd , H-2Kb and H-2Db refolded with either mouse or human beta2m. The change from mouse to human beta2m resulted in a loss of binding of all three MHC class I tetramers to Ly49A and Ly49C, indicating that both these receptors bind to MHC class I in a similar manner, partly involving the beta2m-subunit. To investigate the influence of beta2m on the structure of MHC class 1, in particular in relation to recognition by Ly49 receptors, we crystallized and solved the structures of H-2Db in complex with an LCMV derived peptide and either human or mouse beta2m. This allowed us for the first time to make a comparative analysis of two MHC class I crystal structures where only the 02M subunit differed. Despite over 30% difference in sequence between mouse and human beta2m, the conformation of the peptide and the peptide-binding groove were strikingly similar between the structures. The structures implicate that the lack of Ly49 recognition conferred by human beta2m is a direct consequence of the change from a glutamine to a glycine at position 29 in human beta2m, rather than distal conformational changes. Finally, we identified two heat shock protein 60 (hsp60) derived peptides that readily bind to HLA-E. We demonstrated that HLA-E in complex with these peptides abrogated recognition by the inhibitory CD94/NKG2A receptor, both in binding assays and functional assays. Our results suggest that there is an increased proportion of HLA-E molecules in complex with non-protective hsp60-derived peptides during cellular stress, and consequently a reduced inhibition of CD94/NKG2A+ NK cells. This phenomenon, which we term stress-induced peptide interference (SPI), provides a novel mechanism for NK cells to detect stressed cells in a peptide-dependent manner. In conclusion, our data supports the notion that both human and mouse NK cells have evolved a repertoire of MHC class I specific receptors which are sensitive to perturbations in all subcomponents of the MHC class I molecule.
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| 15. |
- Mold, Jeff E., et al.
(author)
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Cell generation dynamics underlying naive T-cell homeostasis in adult humans
- 2019
-
In: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 17:10
-
Journal article (peer-reviewed)abstract
- Thymic involution and proliferation of naive T cells both contribute to shaping the naive T-cell repertoire as humans age, but a clear understanding of the roles of each throughout a human life span has been difficult to determine. By measuring nuclear bomb test-derived C-14 in genomic DNA, we determined the turnover rates of CD4(+) and CD8(+) naive T-cell populations and defined their dynamics in healthy individuals ranging from 20 to 65 years of age. We demonstrate that naive T-cell generation decreases with age because of a combination of declining peripheral division and thymic production during adulthood. Concomitant decline in T-cell loss compensates for decreased generation rates. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of CD4+ naive T-cell turnover, using mass cytometry to profile candidate signaling pathways involved in T-cell activation and proliferation relative to CD31 expression, a marker of thymic proximity for the CD4+ naive T-cell population. We show that basal nuclear factor kappa B (NF-kappa B) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-kappa B signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-kappa B phosphorylation in CD4(+)CD31(-) naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naive T-cell turnover as a putative regulator of naive T-cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T-cell clones that accumulate with age.
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| 16. |
- Mold, Jeff E., et al.
(author)
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Clonally heritable gene expression imparts a layer of diversity within cell types
- 2024
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In: Cell systems. - : Elsevier BV. - 2405-4720. ; 15:2, s. 149-
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Journal article (peer-reviewed)abstract
- Cell types can be classified according to shared patterns of transcription. Non-genetic variability among individual cells of the same type has been ascribed to stochastic transcriptional bursting and transient cell states. Using high-coverage single-cell RNA profiling, we asked whether long-term, heritable differences in gene expression can impart diversity within cells of the same type. Studying clonal human lymphocytes and mouse brain cells, we uncovered a vast diversity of heritable gene expression patterns among different clones of cells of the same type in vivo. We combined chromatin accessibility and RNA profiling on different lymphocyte clones to reveal thousands of regulatory regions exhibiting interclonal variation, which could be directly linked to interclonal variation in gene expression. Our findings identify a source of cellular diversity, which may have important implications for how cellular populations are shaped by selective processes in development, aging, and disease. A record of this paper's transparent peer review process is included in the supplemental information.
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| 17. |
- Mold, Jeff E., et al.
(author)
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Divergent clonal differentiation trajectories establish CD8(+) memory T cell heterogeneity during acute viral infections in humans
- 2021
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 35:8
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Journal article (peer-reviewed)abstract
- The CD8(+) T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogeneous repertoire of effector and memory cells. How individual T cell clones contribute to this heterogeneity throughout immune responses remains largely unknown. In this study, we longitudinally track human CD8(+) T cell clones expanding in response to yellow fever virus (YFV) vaccination at the single-cell level. We observed a drop in clonal diversity in blood from the acute to memory phase, suggesting that clonal selection shapes the circulating memory repertoire. Clones in the memory phase display biased differentiation trajectories along a gradient from stem cell to terminally differentiated effector memory fates. In secondary responses, YFV- and influenza-specific CD8(+) T cell clones are poised to recapitulate skewed differentiation trajectories. Collectively, we show that the sum of distinct clonal phenotypes results in the multifaceted human T cell response to acute viral infections.
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| 18. |
- Renoux, Virginie, et al.
(author)
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Identification of a Human Natural Killer Cell Lineage-Restricted Progenitor in Fetal and Adult Tissues.
- 2015
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In: Immunity. - : Elsevier BV. - 1074-7613 .- 1097-4180. ; 43:2, s. 394-407
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Journal article (peer-reviewed)abstract
- Natural killer (NK) cells are cytotoxic lymphocytes and play a vital role in controlling viral infections and cancer. In contrast to B and T lymphopoiesis where cellular and regulatory pathways have been extensively characterized, the cellular stages of early human NK cell commitment remain poorly understood. Here we demonstrate that a Lin(-)CD34(+)CD38(+)CD123(-)CD45RA(+)CD7(+)CD10(+)CD127(-) population represents a NK lineage-restricted progenitor (NKP) in fetal development, umbilical cord blood, and adult tissues. The newly identified NKP has robust NK cell potential both in vitro and in vivo, generates functionally cytotoxic NK cells, and lacks the ability to produce T cells, B cells, myeloid cells, and innate lymphoid-like cells (ILCs). Our findings identify an early step to human NK cell commitment and provide new insights into the human hematopoietic hierarchy.
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| 19. |
- Reu, Pedro, et al.
(author)
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Human T cell lifespan
- 2013
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In: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 190, s. P1284-
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Journal article (other academic/artistic)
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| 20. |
- Sountoulidis, Alexandros, et al.
(author)
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A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung
- 2023
-
In: Nature Cell Biology. - : Springer Nature. - 1465-7392 .- 1476-4679.
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Journal article (peer-reviewed)abstract
- Sountoulidis et al. provide a spatial gene expression atlas of human embryonic lung during the first trimester of gestation and identify 83 cell identities corresponding to stable cell types or transitional states. The lung contains numerous specialized cell types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a comprehensive topographic atlas of early human lung development. Here we report 83 cell states and several spatially resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated single-cell RNA sequencing and spatially resolved transcriptomics into a web-based, open platform for interactive exploration. We show distinct gene expression programmes, accompanying sequential events of cell differentiation and maturation of the secretory and neuroendocrine cell types in proximal epithelium. We define the origin of airway fibroblasts associated with airway smooth muscle in bronchovascular bundles and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.
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| 21. |
- Van Hemelrijck, Mieke, et al.
(author)
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Calcium Intake and Serum Concentration in Relation to Risk of Cardiovascular Death in NHANES III
- 2013
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4, s. e61037-
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Journal article (peer-reviewed)abstract
- BACKGROUND: Evidence for an association between calcium intake and risk of cardiovascular death remains controversial. By assessing dietary intake, use of supplements, and serum levels of calcium, we aimed to disentangle this link in the third National Health and Nutrition Examination Survey (NHANES III).METHODS: Mortality linkage of NHANES III to death certificate data for those aged 17 years or older (n = 20,024) was used to estimate risk of overall cardiovascular death as well as death from ischemic heart disease (IHD), acute myocardial infarction (AMI), heart failure (HF), and cerebrovascular disease (CD) with multivariate Cox proportional hazards regression analysis.RESULTS: About 10.0% of the population died of cardiovascular disease and the majority (5.4%) died of IHD. There was increased risk of overall CVD death for those in the bottom 5% of serum calcium compared to those in the mid 90% (HR: 1.51 (95% CI: 1.03-2.22)). For women there was a statistically significant increased risk of IHD death for those with serum calcium levels in the top 5% compared to those in the mid 90% (HR: 1.72 (95%CI: 1.13-2.61)), whereas in men, low serum calcium was related to increased IHD mortality (HR: 2.32 (95% CI 1.14-3.01), Pinteraction: 0.306). No clear association with CVD death was observed for dietary or supplemental calcium intake.CONCLUSIONS: Calcium as assessed by serum concentrations is involved in cardiovascular health, though differential effects by sex may exist. No clear evidence was found for an association between dietary or supplementary intake of calcium and cardiovascular death.
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| 22. |
- Zimmer, Christine L., et al.
(author)
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A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells
- 2021
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In: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:599
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Journal article (peer-reviewed)abstract
- The human biliary system, a mucosal barrier tissue connecting the liver and intestine, is an organ often affected by serious inflammatory and malignant diseases. Although these diseases are linked to immunological processes, the biliary system represents an unexplored immunological niche. By combining endoscopy-guided sampling of the biliary tree with a high-dimensional analysis approach, comprehensive mapping of the human biliary immunological landscape in patients with primary sclerosing cholangitis (PSC), a severe biliary inflammatory disease, was conducted. Major differences in immune cell composition in bile ducts compared to blood were revealed. Furthermore, biliary inflammation in patients with PSC was characterized by high presence of neutrophils and T cells as compared to control individuals without PSC. The biliary T cells displayed a CD103(+)CD69(+) effector memory phenotype, a combined gut and liver homing profile, and produced interleukin-17 (IL-17) and IL-22. Biliary neutrophil infiltration in PSC associated with CXCL8, possibly produced by resident T cells, and CXCL16 was linked to the enrichment of T cells. This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders.
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