Research – Regulation of gene expression in the immune system

Our Research

The immune system distinguishes between self and non-self but also between different types of non-self such as viruses and worms. T helper (Th) cells (CD4+) have a fundamental role in that challenge; following their first interaction with a pathogen, Th cells can differentiate into regulatory or effector lineages that differentially express cytokine genes. The effector lineages Th1, Th2, and Th17 are characterized by the expression of the signature cytokines Interferon g (IFNg), Interleukin-4 (IL-4), and Interleukin-17 (IL-17), respectively. IFNg exerts protective functions in microbial infections and is observed clinically in cases of autoimmune diseases. IL-4 is strongly apparent in parasitic infections, and is associated with allergic reactions. IL-17 plays a role in the eradication of extracellular pathogens, but inappropriate responses can lead to autoimmunity.

Following differentiation, Th cells may enter a resting state, in which they do not express cytokines; nonetheless, they ‘remember’ their transcriptional program and express the appropriate set of cytokines in response to subsequent antigen stimulation. However, this process is more flexible than previously appreciated and under specific circumstances, Th cells can gain the expression of the opposing cytokines or even re-differentiate toward other Th lineages. This plasticity probably assists the immune system to cope with new immunological challenges.

Since immunological diseases such as autoimmunity and allergy are associated with aberrant expression of cytokines in Th cells, elucidation of the epigenetic regulation of these genes can facilitate the development of novel therapies. We study the epigenetic regulation of differentiated murine and human Th cells, especially as regard to the function of the polycomb group proteins.

Dysregulation of the immune function is associated with many other human diseases, and we are also interested in some aspects of the connections between the immune system, brain, and the microbiome. We are also studying inflammatory processes associated with heart failure and cardiomyopathy.


Ezh2 harnesses the intranuclear actin cytoskeleton to remodel chromatin in differentiating Th cells.

Moran Titelbaum 1Boris Brant 1Daniel Baumel 1Alina Burstein-Willensky 1Shira Perez 1Yiftah Barsheshet 1Orly Avni 1
 2021 Sep 9;24(10):103093

Following their first interaction with the antigen, quiescent naive T-helper (Th; CD4+) cells enlarge, differentiate, and proliferate; these processes are accompanied by substantial epigenetic alterations. We showed previously that the epigenetic regulators the polycomb-group (PcG) proteins have a dual function as both positive and negative transcriptional regulators; however, the underlying mechanisms remain poorly understood. Here, we demonstrate that during Th cell differentiation the methyltransferase activity of the PcG protein Ezh2 regulates post-transcriptionally inducible assembly of intranuclear actin filaments. These filaments are colocalized with the actin regulators Vav1 and WASp, vertically oriented to the T cell receptor, and intermingle with the chromatin fibers. Ezh2 and Vav1 are observed together at chromatin-actin intersections. Furthermore, the inducible assembly of nuclear actin filaments is required for chromatin spreading and nuclear growth. Altogether these findings delineate a model in which the epigenetic machinery orchestrates the dynamic mechanical force of the intranuclear cytoskeleton to reorganize chromatin during differentiation.




Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome.

 2017 Mar;9(3):319-336. doi: 10.15252/emmm.201606523.

Dilated cardiomyopathy (DCM) is a life-threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4-30 months from four families, were diagnosed with DCM associated with mild skin, teeth, and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at PPP1R13L encoding the iASPP protein was identified in three infants and in the mother of the other two. Patients’ fibroblasts and PPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to lipopolysaccharide, as well as Ppp1r13l-knocked down murine cardiomyocytes and hearts of Ppp1r13l-deficient mice. The hypersensitivity to lipopolysaccharide was NF-κB-dependent, and its inducible binding activity to promoters of pro-inflammatory cytokine genes was elevated in patients’ fibroblasts. RNA sequencing of Ppp1r13l-knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in Ppp1r13l-deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined PPP1R13L as the gene underlying a novel autosomal-recessive cardio-cutaneous syndrome in humans and strongly suggest that the fatal DCM during infancy is a consequence of failure to regulate transcriptional pathways necessary for tuning cardiac threshold response to common inflammatory stressors.


Schistosomal extracellular vesicle-enclosed miRNAs modulate host T helper cell differentiation.

2020 Jan 7;21(1):e47882. doi: 10.15252/embr.201947882. Epub 2019 Dec 11.

During the chronic stage of Schistosoma infection, the female lays fertile eggs, triggering a strong anti-parasitic type 2 helper T-cell (Th2) immune response. It is unclear how this Th2 response gradually declines even though the worms live for years and continue to produce eggs. Here, we show that Schistosoma mansoni downregulates Th2 differentiation in an antigen-presenting cell-independent manner, by modulating the Th2-specific transcriptional program. Adult schistosomes secrete miRNA-harboring extracellular vesicles that are internalized by Th cells in vitro. Schistosomal miRNAs are found also in T helper cells isolated from Peyer’s patches and mesenteric lymph nodes of infected mice. In T helper cells, the schistosomal miR-10 targets MAP3K7 and consequently downmodulates NF-κB activity, a critical transcription factor for Th2 differentiation and function. Our results explain, at least partially, how schistosomes tune down the Th2 response, and provide further insight into the reciprocal geographic distribution between high prevalence of parasitic infections and immune disorders such as allergy. Furthermore, this worm-host crosstalk mechanism can be harnessed to develop diagnostic and therapeutic approaches for human schistosomiasis and Th2-associated diseases.


Social-Stress-Responsive Microbiota Induces Stimulation of Self-Reactive Effector T Helper Cells.

 2019 May 14;4(4). pii: e00292-18. doi: 10.1128/mSystems.00292-18. eCollection 2019 Jul-Aug.

Stressful life events are considered a risk factor for autoimmune disorders, though the mechanisms are unclear. Here we demonstrate that chronic social stress induces virulence-associated transcriptional patterns in the murine gut microbiota. The stress-influenced microbiota increased the presence of effector T helper cells in the mesenteric lymph nodes, including myelin-autoreactive cells. Inhibition of the bacterial quorum sensor QseC, which is also responsive to norepinephrine, diminished the presence of effector T helper cells and bacteria such as Acinetobacter in the mesenteric lymph nodes, without remarkably affecting the gut microbial composition. Together, our results delineate a model in which the immune reaction to stress-responsive microbiota may compromise tolerance to self and therefore may increase the risk for autoimmune diseases in susceptible individuals. IMPORTANCE How do stressful life events increase the risk for autoimmune disorders? Here we show that chronic social stress in mice promotes the expression of virulent genes in the gut microbiota and alters the microbial translocation into the mesenteric lymph nodes. Our results also suggest that the consequent immune response to the stress-affected microbiota may endanger the tolerance for self. The presence of specific translocated bacteria and the immune response in the mesenteric lymph nodes can be diminished using an inhibitor of the bacterial communication system without drastically affecting the gut microbial composition as antibiotics do.




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