Biology subjects

Mattsson, M.

Publications and source records attributed to Mattsson, M..

3 recordsLinked to original sources

bioRxiv2020

Activation of the myeloid checkpoint inhibitor LILRB3 (ILT5) elicits profound immununomodulation

Despite advances in identifying the key immunoregulatory roles of many of the human leukocyte immunoglobulin (Ig)-like receptor (LILR) family members, the function of the inhibitory molecule LILRB3 (ILT5, CD85a, LIR3) remains unclear. Studies indicate a predominant myeloid expression; however, high homology within the LILR family and a relative paucity of reagents have hindered progress for this receptor. To investigate its function and potential immunomodulatory capacity, a panel of LILRB3-specific monoclonal antibodies (mAb) was generated. LILBR3-specific mAb bound to discrete epitopes in either Ig-like domain two or four. LILRB3 ligation on primary human monocytes by agonistic mAb resulted in phenotypic and functional changes, leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Importantly, agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells. Our findings reveal powerful immunosuppresive functions of LILRB3 and identify it as an important myeloid checkpoint receptor.

immunology↗

bioRxiv2018

Single-cell analysis reveals the KIT D816V mutation in hematopoietic stem and progenitor cells in systemic mastocytosis

Background: Systemic mastocytosis (SM) is a hematological disease characterized by organ infiltration by neoplastic mast cells. Almost all SM patients have a mutation in the gene encoding the tyrosine kinase receptor KIT causing a D816V substitution and autoactivation of the receptor. Mast cells and CD34+ hematopoietic progenitors can carry the mutation, however, in which progenitor cell subset the mutation arises is unknown. We aimed to investigate the distribution of the D816V mutation in single mast cells and single hematopoietic stem and progenitor cells. Methods: Fluorescence-activated single-cell index sorting and D816V mutation assessment were applied to analyze mast cells and more than 10,000 CD34+ bone marrow progenitors across 10 hematopoietic progenitor subsets. In vitro assays verified cell-forming potential. Findings: We found that in SM 60-99% of the mast cells harbored the D816V mutation. Despite increased frequencies of mast cells in SM patients compared with control subjects, the hematopoietic progenitor subset frequencies were comparable. Nevertheless, the mutation could be detected throughout the hematopoietic landscape of SM patients, from hematopoietic stem cells to more lineage-primed progenitors. In addition, we demonstrate that Fc{varepsilon}RI+ bone marrow progenitors exhibit mast cell-forming potential, and we describe aberrant CD45RA expression on SM mast cells for the first time. Interpretation: The KIT D816V mutation arises in early hematopoietic stem and progenitor cells and the mutation frequency is approaching 100% in mature mast cells, which express the aberrant marker CD45RA.

immunology↗

bioRxiv2018

Conjugation factors controlling F-plasmid antibiotic resistance transmission

The rapid horizontal transmission of many antibiotic resistance genes between bacterial host cells on conjugative plasmids is a major cause of the accelerating antibiotic resistance crisis. Preventing understanding and targeting conjugation, there currently are no experimental platforms for fast and cost-efficient screening of genetic effects on antibiotic resistance transmission by conjugation. We introduce a novel experimental framework to screen for conjugation based horizontal transmission of antibiotic resistance between >60.000 pairs of cell populations in parallel. Plasmid-carrying donor strains are constructed in high throughput. We then mix the resistance plasmid carrying donors with recipients in a design where only transconjugants can reproduce, measure growth in dense intervals and extract transmission times as the growth lag. As proof-of-principle, we exhaustively explored chromosomal genes controlling F plasmid donation within E. coli populations, by screening the Keio deletion collection at high replication. We recover all six known chromosomal gene mutants affecting conjugation and identify >50 novel factors, all of which diminish antibiotic resistance transmission. We verify 10 of the novel genes effects in a liquid mating assay. The new framework holds great potential for exhaustive disclosing of candidate targets for helper drugs that delay resistance development in patients and societies and improves the longevity of current and future antibiotics.

microbiology↗