Transcriptional delineation of human ILC heterogeneity and plasticity reveals potential targets for treatment of inflammatory conditions

Friday 28 April 2017, 1.00PM

Speaker: Dr Jenny Mjösberg, Karolinska Institute, Stockholm, Sweden

Innate lymphoid cells (ILCs) are increasingly appreciated as important players in homeostasis and inflammation. Substantial plasticity and heterogeneity among ILC populations has been reported. We have recently delineated heterogeneity among human ILCs through single-cell RNA sequencing of human tonsil CD127+ ILCs and natural killer (NK) cells, revealing molecular pathways and components selectively expressed in particular ILC subsets and uncovering three transcriptionally and functionally different subpopulations of ILC3. These efforts provide interesting targets for treatment of inflammatory conditions. One such target was PGE2, where ILC2 express high levels of the PGE2 receptors EP2 and EP4. PGE2 is a bioactive lipid that plays protective roles in the lung, particularly during allergic inflammation. We find that PGE2 limits proliferation and cytokine production from human ILC2 through the combined action of the EP2 and EP4 receptors. Thus, selective EP2 and EP4 receptor agonism might serve as promising therapeutic approach in treating allergic diseases by suppressing ILC2 function. Moreover, through transcriptional analyses, we also find that ILC3 stimulated with IL-23 plus IL-1β upregulates the vitamin D receptor (VDR), rendering ILC3 responsive to vitamin D. In cytokine stimulated ILC3, Vitamin D repressed the IL-23R pathway and consequently the IL-23-regulated production of IL-22, IL-17F and GM-CSF while simultaneously shifting ILC3 cytokine production to innate-type cytokines including IL-6, IL-8 and MIPs. In the light of the beneficial targeting of IL-23/12 in IBD, vitamin D may inhibit the IL-23R pathway, providing a novel mechanism for how ILC3 could be manipulated to regulate intestinal inflammation. In summary, our transcriptional analyses have uncovered heterogeneity and functional plasticity of human ILC3, with implications for several chronic inflammatory diseases including allergy/asthma and IBD. 

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More on the Jenny Mjösberg group

This seminar is part of the Manchester/York seminar series.  

 

The host for this seminar is Marika Kullberg.  

Location: K/018

Email: cii@york.ac.uk

Telephone: 01904 328845

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