Asbjørn Christophersen

Bio: Asbjørn Christophersen is an academic researcher from University of Oslo. The author has contributed to research in topics: Gluten & T-cell receptor. The author has an hindex of 12, co-authored 22 publications receiving 463 citations. Previous affiliations of Asbjørn Christophersen include Oslo University Hospital.

Distinct phenotype of CD4 + T cells driving celiac disease identified in multiple autoimmune conditions

Abstract: Combining HLA-DQ-gluten tetramers with mass cytometry and RNA sequencing analysis, we find that gluten-specific CD4+ T cells in the blood and intestines of patients with celiac disease display a surprisingly rare phenotype. Cells with this phenotype are also elevated in patients with systemic sclerosis and systemic lupus erythematosus, suggesting a way to characterize CD4+ T cells specific for disease-driving antigens in multiple autoimmune conditions.

Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease

Abstract: Little is known about the repertoire dynamics and persistence of pathogenic T cells in HLA-associated disorders. In celiac disease, a disorder with a strong association with certain HLA-DQ allotypes, presumed pathogenic T cells can be visualized and isolated with HLA-DQ:gluten tetramers, thereby enabling further characterization. Single and bulk populations of HLA-DQ:gluten tetramer-sorted CD4+ T cells were analyzed by high-throughput DNA sequencing of rearranged TCR-α and -β genes. Blood and gut biopsy samples from 21 celiac disease patients, taken at various stages of disease and in intervals of weeks to decades apart, were examined. Persistence of the same clonotypes was seen in both compartments over decades, with up to 53% overlap between samples obtained 16 to 28 years apart. Further, we observed that the recall response following oral gluten challenge was dominated by preexisting CD4+ T cell clonotypes. Public features were frequent among gluten-specific T cells, as 10% of TCR-α, TCR-β, or paired TCR-αβ amino acid sequences of total 1813 TCRs generated from 17 patients were observed in 2 or more patients. In established celiac disease, the T cell clonotypes that recognize gluten are persistent for decades, making up fixed repertoires that prevalently exhibit public features. These T cells represent an attractive therapeutic target.

KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19

Abstract: In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases. Description Say a KIR-full goodbye to autoimmunity Ly49+CD8+ T cells are a subset of CD8+ T cells that show immunoregulatory activity in mice. Li et al. report the existence of a similar CD8+ T cell subset in humans that expresses killer cell immunoglobulin-like receptors (KIRs), a functional parallel of the mouse Ly49 family (see the Perspective by Levescot and Bensussan). These cells, which can suppress self-reactive CD4+ T cells, were more abundant in patients with autoimmune conditions such as celiac disease, multiple sclerosis, and lupus, as well as in patients infected with influenza virus or severe acute respiratory syndrome coronavirus 2. When mice selectively deficient in Ly49+CD8+ T cells were infected with viruses, they showed normal antiviral immune responses but eventually developed symptoms of autoimmune disease. KIR+CD8+ T cells may therefore be an important therapeutic target for the control of autoimmune diseases such as “long COVID” that emerge after viral infections. —STS Regulatory CD8+ T cells act to suppress pathogenic T cells in autoimmune and infectious diseases in mice and humans. INTRODUCTION Previous studies have identified Ly49+CD8+ T cells as a CD8+ T cell subset with regulatory functions in mice. These cells can suppress myelin oligodendrocyte glycoprotein (MOG)–specific pathogenic CD4+ T cells through their cytolytic activity and thereby ameliorate experimental autoimmune encephalomyelitis (EAE). However, whether a similar CD8+ regulatory T cell subset exists in humans and whether its suppressive activity extends beyond autoimmune diseases to play a more general role in peripheral tolerance remains to be determined. RATIONALE Because killer cell immunoglobulin-like receptors (KIRs) are the evolutionary counterpart of the mouse Ly49 family in humans, we investigated whether KIR+CD8+ T cells are the phenotypic and functional equivalent of mouse Ly49+CD8+ T cells. We assessed the frequency of KIR+CD8+ T cells in human autoimmune and infectious diseases and analyzed their transcriptional profiles as well as T cell receptor (TCR) repertoires. Moreover, we developed an in vitro functional assay to test their regulatory functions on gliadin-specific disease-driving CD4+ T cells from patients with celiac disease (CeD) and to study the mechanisms of suppression. To further elucidate their role in infectious diseases, we analyzed the effects of selective ablation of their murine counterpart on the antiviral responses during infection and tissue pathology after resolution of viral infection. RESULTS The frequency of KIR+CD8+ T cells was higher in the blood and inflamed tissues of patients with multiple autoimmune diseases compared with those of healthy controls. Furthermore, the increase of duodenal KIR+CD8+ T cells positively correlated with disease activity in CeD. In vitro, KIR+CD8+ T cells were able to specifically eliminate gliadin-specific pathogenic CD4+ T cells from the leukocytes of CeD patients through their cytotoxicity in a class I major histocompatibility complex (MHC)–dependent manner. Moreover, our RNA sequencing (RNA-seq) analysis revealed many similarities between human KIR+CD8+ T cells and mouse Ly49+CD8+ T cells, which suggests that KIR+CD8+ T cells are the functional and phenotypic equivalents of mouse Ly49+CD8+ T cells in humans. The expression of inhibitory KIR receptors appeared to suppress the activation and cytotoxic functions of KIR+CD8+ T cells. Moreover, elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells (Tregs), were also observed in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)– or influenza-infected patients and correlated with vasculitis in COVID-19 patients. Notably, expanded KIR+CD8+ T cells from healthy subjects and different diseases displayed shared phenotypes and similar TCR sequences as revealed by single-cell RNA-seq and TCR sequencing (TCR-seq). Finally, the selective depletion of Ly49+CD8+ T cells in virus-infected mice did not interfere with the antiviral responses but resulted in exacerbated autoimmunity after infection, demonstrating the critical role that this subset of CD8+ Tregs plays in controlling harmful self-reactivity in infectious diseases. CONCLUSION We identify KIR+CD8+ T cells as an important regulatory T cell subset in humans. They are induced as part of the response during an autoimmune reaction or infection and may act as a negative feedback mechanism to specifically suppress the self-reactive or otherwise pathogenic cells without affecting the immune responses against pathogens. This subset of CD8+ Tregs appears to play an important role in maintaining peripheral tolerance, which is distinct from and likely complementary to that of CD4+ Tregs. Our findings also provide insights into understanding the relationship between autoimmunity and infectious diseases and into the development of potential therapeutic approaches targeting KIR+CD8+ T cells to suppress undesirable self-reactivity in autoimmune disorders and infectious diseases. The proposed role of CD8+ regulatory T cells in peripheral tolerance. KIR+CD8+ T cells are the equivalent of mouse Ly49+CD8+ T cells in humans, with similar regulatory functions. During an infection, this kind of CD8+ regulatory T cell is induced and suppresses those CD4+ T cells with a strong reactivity to self, which may cause autoimmunity without interfering with the immune responses against pathogens.

Tetramer-visualized gluten-specific CD4+ T cells in blood as a potential diagnostic marker for coeliac disease without oral gluten challenge

Abstract: Background: Diagnosing coeliac disease (CD) can be challenging, despite highly specific autoantibodies and typical mucosal changes in the small intestine. The T-cell response to gluten is a hallmark of the disease that has been hitherto unexploited in clinical work-up. Objectives: We aimed to develop a new method that directly visualizes and characterizes gluten-reactive CD4þ T cells in blood, independently of gluten challenge, and to explore its diagnostic potential. Methods: We performed bead-enrichment of DQ2.5-glia-a1a and DQ2.5-glia-a2 tetramerþ cells in the blood of control individuals, treated (TCD) and untreated patients (UCD). We visualized these cells by flow cytometry, sorted them and cloned them. We assessed their specificity by antigen stimulation and re-staining with tetramers. Results: We detected significantly more gliadin-tetramerþ CD4þ effector memory T cells (TEM) in UCD and TCD patients, compared to controls. Significantly more gliadin-tetramerþ TEM in the CD patients than in controls expressed the guthoming marker integrin-b7. Conclusion: Quantification of gut-homing, gluten-specific TEM in peripheral blood, visualized with human leukocyte antigen (HLA) -tetramers, may be used to distinguish CD patients from healthy individuals. Easy access to gluten-reactive blood T cells from diseased and healthy individuals may lead to new insights on the disease-driving CD4þ T cells in CD.

VDJtools: Unifying post-analysis of T cell receptor repertoires

Abstract: Despite the growing number of immune repertoire sequencing studies, the field still lacks software for analysis and comprehension of this high-dimensional data. Here we report VDJtools, a complementary software suite that solves a wide range of T cell receptor (TCR) repertoires post-analysis tasks, provides a detailed tabular output and publication-ready graphics, and is built on top of a flexible API. Using TCR datasets for a large cohort of unrelated healthy donors, twins, and multiple sclerosis patients we demonstrate that VDJtools greatly facilitates the analysis and leads to sound biological conclusions. VDJtools software and documentation are available at https://github.com/mikessh/vdjtools.

Pathway paradigms revealed from the genetics of inflammatory bowel disease.

Abstract: Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.

Autoimmunity and organ damage in systemic lupus erythematosus

Abstract: Impressive progress has been made over the last several years toward understanding how almost every aspect of the immune system contributes to the expression of systemic autoimmunity. In parallel, studies have shed light on the mechanisms that contribute to organ inflammation and damage. New approaches that address the complicated interaction between genetic variants, epigenetic processes, sex and the environment promise to enlighten the multitude of pathways that lead to what is clinically defined as systemic lupus erythematosus. It is expected that each patient owns a unique 'interactome', which will dictate specific treatment.

Maternal Immunological Adaptation During Normal Pregnancy

Abstract: The risk and severity of specific infections are increased during pregnancy due to a combination of physiological and immunological changes. Characterizing the maternal immune system during pregnancy is important to understand how the maternal immune system maintains tolerance towards the allogeneic fetus. This may also inform strategies to prevent maternal fatalities due to infections and optimize maternal vaccination to best protect the mother-fetus dyad and the infant after birth. In this review, we describe what is known about the immunological changes that occur during a normal pregnancy.

Predicting HLA class II antigen presentation through integrated deep learning

Abstract: Accurate prediction of antigen presentation by human leukocyte antigen (HLA) class II molecules would be valuable for vaccine development and cancer immunotherapies. Current computational methods trained on in vitro binding data are limited by insufficient training data and algorithmic constraints. Here we describe MARIA (major histocompatibility complex analysis with recurrent integrated architecture; https://maria.stanford.edu/ ), a multimodal recurrent neural network for predicting the likelihood of antigen presentation from a gene of interest in the context of specific HLA class II alleles. In addition to in vitro binding measurements, MARIA is trained on peptide HLA ligand sequences identified by mass spectrometry, expression levels of antigen genes and protease cleavage signatures. Because it leverages these diverse training data and our improved machine learning framework, MARIA (area under the curve = 0.89–0.92) outperformed existing methods in validation datasets. Across independent cancer neoantigen studies, peptides with high MARIA scores are more likely to elicit strong CD4+ T cell responses. MARIA allows identification of immunogenic epitopes in diverse cancers and autoimmune disease. A neural network trained on diverse datasets improves prediction of HLA class II epitope presentation.