Jakob Theorell

Karolinska University Hospital | Karolinska

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural k...

Intrathecal synthesis of central nervous system (CNS)-reactive autoantibodies is observed across patients with autoimmune encephalitis (AE), who show multiple residual neurobehavioral deficits and relapses despite immunotherapies. We leveraged two common forms of AE, mediated by leucine-rich glioma inactivated-1 (LGI1) and contactin-associated prot...

Thawing of viably frozen human tissue T cells, ILCs, and NK cells and subsequent single‐cell RNA sequencing reveals that recovery of cellular subclusters is variably impacted. While freeze‐thawing does not alter the transcriptional profiles of cells, it upregulates genes and gene pathways associated with stress and activation. image

Innate lymphoid cells (ILCs) are considered innate counterparts of adaptive T cells; however, their common and unique transcriptional signatures in pediatric inflammatory bowel disease (pIBD) are largely unknown. Here, we report a dysregulated colonic ILC composition in pIBD colitis that correlates with inflammatory activity, including accumulation...

During early pregnancy, decidual innate lymphoid cells (dILCs) interact with surrounding maternal cells and invading fetal extravillous trophoblasts (EVT). Here, using mass cytometry, we characterise five main dILC subsets: decidual NK cells (dNK)1–3, ILC3s and proliferating NK cells. Following stimulation, dNK2 and dNK3 produce more chemokines tha...

How antibodies naturally acquired during Plasmodium falciparum infection provide clinical immunity to blood-stage malaria is unclear. We studied the function of natural killer (NK) cells in people living in a malaria-endemic region of Mali. Multi-parameter flow cytometry revealed a high proportion of adaptive NK cells, which are defined by the loss...

[This corrects the article DOI: 10.3389/fimmu.2017.00723.].

Technological advances have facilitated an exponential increase in the amount of information that can be derived from single cells, necessitating new computational tools that can make such highly complex data interpretable. Here, we introduce DEPECHE, a rapid, parameter free, sparse k-means-based algorithm for clustering of multi- and megavariate s...

Heatmaps comparing the golden standard partitions to the DEPECHE partitions for A) the 32-variate Levine dataset and B) the 35166-variate Björklund dataset. Red color indicates large overlap, blue color indicates low overlap between a gold standard-vs-DEPECHE cluster pair. Numbers in heatmaps denote percent of the golden standard cluster present in...

Algorithm comparisons. For all graphs, the x-axis shows the algorithms and the y-axis shows the Adjusted Rand Index comparing the clustering result with the golden standard clustering. Below each graph is the average computational time in seconds for the benchmarking performed on a laptop computer with 4 2.8 GHz Intel Core i7 processors. A) Subsamp...

The code used generate all figures. (ZIP)

Information on how to retrieve the data used for this study. (PDF)

A comparison of classical K-means, sparse K-means and DEPECHE. A: Overlap between true clusters and clusters generated with classical k-means, sparse K-means, or DEPECHE. Numbers in heatmaps denote percent of the true cluster present in the generated cluster in question. Red color indicates high overlap, blue color low overlap. B: Total loadings fo...

Technological advances have facilitated an exponential increase in the amount of information that can be derived from single cells, necessitating new computational tools that can make this highly complex data interpretable. Here, we introduce DEPECHE, a rapid, parameter free, sparse k-means-based algorithm for clustering of multi-and megavariate si...

Plasmodium falciparum (P.f) infection is a major cause of morbidity and mortality world-wide where symptoms and death occur as a result of the blood stage of the P.f. life cycle. To date, there is no effective blood stage malarial vaccine. Natural Killer (NK) cells are key players in the control of hematopoietic cancers and viral infections, howeve...

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections as well as physiological stress. Cytotoxic lymphocytes combat intracellular infections. Their function is attenuated by stress. Despite numerous studies, the role of cytotoxic lymphocytes in ME/CFS remains unclear. Pr...

Plasmodium falciparum (P.f) infection is a major cause of morbidity and mortality world-wide where symptoms and death occur as a result of the blood stage of the P.f. life cycle. To date, there is no effective blood stage malarial vaccine. Natural Killer (NK) cells are key players in the control of hematopoietic cancers and viral infections, howeve...

Key Points GATA-2 expression is restricted to hematopoietic stem and progenitor cells, leading to NK-cell progenitor deficiency in GATA2 patients. A long-lived or self-renewing pool of adaptive NK cells can persist in patients with GATA2 mutation.

Natural killer (NK) cells have long been considered short-lived effectors of innate immunity. However, recent animal models and human studies suggest that subsets of NK cells have adaptive features. We investigate clonal relationships of various NK-cell subsets, including the adaptive population, by taking advantage of naturally occurring X-linked...

Introduction Myelodysplastic syndromes (MDS) are a group of clonal bone marrow disorders, with dysplasia, cytopenias and increased risk of progression to acute myeloid leukemia. A dysregulated immune system precipitates MDS, and to gain insights into the relevance of cytotoxic T lymphocyte (CTL) in this process, we examined the frequency and functi...

In signaling cascades downstream of NK cell activating receptor engagement, Ca 2+ ions are pivotal second messengers for NK cell cytotoxicity as well as cytokine production. Upon cellular activation, intracellular mobilization of Ca²⁺ ions initially involves depletion of endoplasmic reticulum stores, leading to subsequent Ca²⁺ influx through specif...

Innate lymphoid cells (ILCs) are increasingly appreciated as important participants in homeostasis and inflammation. Substantial plasticity and heterogeneity among ILC populations have been reported. Here we have delineated the heterogeneity of human ILCs through single-cell RNA sequencing of several hundreds of individual tonsil CD127(+) ILCs and...

Natural killer (NK) cells are lymphocytes that participate in different facets of immunity. They can act as innate sentinels through recognition and eradication of infected or transformed target cells, so-called immunosurveillance. In addition, they can contain immune responses through the killing of other activated immune cells, so-called immunore...

Multi-color flow cytometry represents an important tool for characterization of immune cell phenotype and function. In humans, this technique is most often applied to studies of cells obtained from peripheral blood. However, in many human disease conditions, peripheral tissues are the preferred sites for investigation. Such is the case, e.g., in qu...

The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression i...

Objective Recently we serendipitously identified a patient with systemic lupus erythematosus (SLE) who was positive for autoantibodies to CD94/natural killer receptor group 2A (NKG2A). The present study was undertaken to investigate the occurrence and function of autoantibodies targeting lectin-like NK cell receptors in SLE.Methods Sera from 203 SL...

Natural killer (NK) cells mediate defense against neoplastic as well as infected cells. Yet, how their effector functions are affected by the large variety of pharmacological compounds commonly in use has not been investigated systematically. Here, we screened 1,200 in-use or previously approved drugs for their biological effect on freshly isolated...

During childhood, infections with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) can occur in close temporal proximity. Active, as well as latent, CMV infection is associated with enlarged subsets of differentiated natural killer (NK) and cytotoxic T cells. How EBV infection may influence CMV-driven immune differentiation is not known. We found...

Patients with systemic lupus erythematosus (SLE) display an activated type I IFN system due to unceasing IFN-α release from plasmacytoid dendritic cells (pDCs) stimulated by nucleic acid-containing immune complexes (ICs). NK cells strongly promote the IFN-α production by pDCs; therefore, we investigated surface molecules that could be involved in t...

Objectives: To characterize a novel anti-NKG2A autoantibody detected in a patient with SLE during a severe flare, and in a cross-sectional study investigate the occurrence of such autoantibodies in patients with SLE and primary SS (pSS). Methods: Serum or IgG from patients with SLE, pSS and healthy volunteers were assayed for blocking of anti-NK...

Cytomegalovirus (CMV) is a persistent herpesvirus that promotes NKG2C+ Natural Killer (NK) cell differentiation. Highly mature CD57+ NKG2C+ NK cells have been proposed as the equivalent of mouse memory-like NK cells, which have features as long-term persistence and enhanced recall responses. AIM: To examine if co-infection with another common herpe...

Key Points Compared with cytotoxic T cells, NK cells share mechanisms for lytic granule release but more stringently control cytokine production. Analysis of CD57bright cytotoxic T-cell function may prove useful in the diagnosis of primary immunodeficiencies.

Background and objectives Patients with SLE have an activated type I interferon (IFN)-system due to an ongoing IFNα production by plasmacytoid dendritic cells (pDCs) stimulated by nucleic acid-containing immune complexes (ICs). The IFNα production is promoted by NK cells via MIP-1β, and LFA-1-mediated cell-cell contact. Because genome-wide linkage...

With an array of activating and inhibitory receptors, natural killer (NK) cells can specifically eradicate infected and transformed cells. Target cell killing is achieved through directed release of lytic granules. Recognition of target cells also induces production of chemokines and cytokines that can coordinate immune responses. Upon contact with...

An early step in immunosurveillance by cytotoxic lymphocytes is leukocyte functional antigen (LFA)-1-dependent adhesion to target cells, which is promoted by inside-out signals from receptors such as the T cell receptor and a variety of natural killer (NK) cell activating receptors. Inside-out signals induce a conformational change in LFA-1, result...