Selected articles November 2015

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Dynamics of tissue redistribution of human NK cell subsets

 

Tissue Distribution Dynamics of Human NK Cells Inferred from Peripheral Blood Depletion Kinetics after Sphingosine-1-Phosphate Receptor Blockade 

 

M. Mehling, A.-V. Burgener, V. Brinkmann, G. R. Bantug, S. Dimeloe, G. Hoenger, L. Kappos and C. Hess

 

In this study, conducted by researchers in Switzerland, the dynamics of tissue redistribution of human NK cell subsets in a cohort of patients with multiple sclerosis newly treated with the drug fingolimod was investigated.

 

In humans, two main functional subsets, CD56bright and CD56dim are distinguished. They both originate from the bone marrow, but following egress they redistribute in a tissue-specific manner. The dynamics with which these NK cell subsets redistribute to tissues remain unexplored. Here, the researchers took advantage of the mode of action of the drug fingolimod which efficiently blocks spingosine-1-phosphate-directed lymphocyte egress from tissue to blood. By studying depletion kinetics of NK cells in the blood of de novo fingolimod-exposed individuals, the researchers monitored indirectly dynamics of the redistribution of CD56bright and CD56dim NK cells from blood to tissue.

 

During this project the shared first co-authors M. Mehling and AV. Burgener worked at the Immunobiology research group of the Department of Biomedicine (Basel/Switzerland) as a postdoc and a master student, respectively. M Mehling also works as a neurologist at the University Hospital of Basel.

 

M. Mehling was involved in conceptualizing the study and organized most clinical and laboratory-related study logistics. Together, M. Mehling and AV. Burgener performed the experimental work, analysed the data, and conducted statistical analysis. Both were significantly involved in preparing the manuscript.

 

– For us, the main findings were the differential depletion kinetics of CD56bright NK cells and CD56dim NK cells cells following the first dose of fingolimod as this indicates a differential tissue distribution of these NK cell subpopulations. Specifically, this indicates that CD56bright NK cells cells preferentially home to secondary lymphoid organs where they are trapped by fingolimod, whereas CD56dim NK cells distribute mostly to non-lymphoid tissue.

 

In all, these data add basic insight to the understanding of the tissue distribution dynamics of NK cell in humans and by this to the immune surveillance process. 

 

The researchers enjoyed this project that can have an impact on patients.

 

– The most fascinating moment was when we realized that we were able to capture with our approach differential depletion kinetics in NK cell subsets following the first dose of fingolimod. It was truly exciting to see that our hypothesis was correct and that we could generate biologically meaningful data while immunomonitoring humans starting with this selective immunomodulatory therapy.

 

 

 

New insights into the regulation of BCR signalling

 

IRF4 Deficiency Leads to Altered BCR Signalling Revealed by Enhanced PI3K Pathway, Decreased SHIP Expression and Defected Cytoskeletal Responses

 

P. M. Budzyńska, M. Niemelä, A.V. Sarapulov, M.K. Kyläniemi, K.-P. Nera, S. Junttila, A. Laiho, P.K. Mattila, J. Alinikula and O. Lassila

 

Here, a group from Finland show that transcription factor interferon regulator factor 4 (IRF4) has an important role in the regulation of BCR signalling and help to shed light on the molecular mechanisms of B cell development and germinal centre response.

 

Graded expression of IRF4 regulates B cell development and is critical for plasma cell differentiation. Here, researchers have characterized molecular targets of IRF4 in B cells, by establishing an IRF4-deficient cell line.

 

Paulina Budzynska is a PhD student in the research group of Professor Olli Lassila at the Department of Medical Microbiology and Immunology at the University of Turku. This article is a part of her PhD thesis.

 

– When I joined Olli Lassila’s laboratory I started this project by writing a study plan, I designed and performed most of the experiments, analysed the obtained data and wrote the first draft of the manuscript, she says. Furthermore, I was responsible for conducting active and fruitful collaboration with other authors especially with Dr Pieta Mattila whose research expertise is in the lymphocyte cytoskeleton and advanced microscopy.

 

Using the IRF4-deficient cell line Paulina Budzynska and co-workers found a compromised B cell receptor signalling in the absence of IRF4. In more detail, IRF4 disruption upregulated the BCAP and downregulated SHIP expression, leading to strongly enhanced activity of PI3K/Akt pathway upon BCR ligation. It was also found that attenuated early BCR signalling events in stimulated IRF4-deficient cells severely compromised signalling to the actin cytoskeleton.

 

– I think that this study advances our knowledge about the transcriptional role of IRF4 in the regulation of BCR signalling and helps to shed light on the molecular mechanisms of B cell development and activation response, since in physiological conditions vast majority of germinal center B cells lack IRF4 expression, Paulina Budzynska says. In addition, the study provides insights into how B cells might sense the antigen in germinal centers.

 

Paulina Budzynska appreciate spending time in the lab.

 

– I really enjoyed performing the experiments in this study. The greatest fun was waiting in the dark room for results from Western blots. It was so exciting to be the first to see the unknown, she concludes.