Van Bekkum thesis award 2016 for Jochem Bernink

Jochem Bernink wins this year's NVVI Thesis Award for 'The biology of human Innate Lymphoid Cells' (ILC). These ILCs are relatively rare in blood and tissue. They have similarities with other lymphocyte types. That is why they have remained under the radar until recently. Bernink identified the ILC1 subset and contributed to unravelling the complex interaction mechanism in which the ILCs play their part. He especially emphasizes the reversible plasticity of ILCs and describes what this means for immunopathology-mediated diseases.

Van Bekkum thesis award 2016 for Jochem Bernink
The remarkable plasticity of Innate Lymphoid Cells

mojoimagealt-5938-altUnder the epithelial surface of the intestines and lungs lies a layer of sterile mucous tissue. It is filled with immune cells that control the epithelial microflora. The three ILC subsets ILC1, ILC2 and ILC3 which have been described so far play an important role in this regard. Advanced analysis methods have enabled their identification in recent years. Bernink: “It turns out the ILCs can respond instantly to changes in their environment, for instance by initiating an immune response that protects or –when not properly regulated – can cause severe immunopathology.”   

Reversibility
ILC2 and ILC3 are important for numerous processes in healthy tissue to safeguard homeostasis. In case of an infection, however, the number of ILC1 rises quickly. This subset was discovered only four years ago by Bernink et al., as it only occurs in inflamed tissue. Bernink: “Our research has shown that ILC1 can initiate a protective immune response by instant production of interferon gamma (IFN-γ). Growing numbers of ILC1 coincide with decline of ILC2 and ILC3. We have shown that in a pro-inflammatory environment these subsets in fact transdifferentiate to ILC1. The cytokine IL-12, produced during stress reactions, initiates this process as it binds to the Il-12 receptor which comes to expression on ILC2 and ILC3.”
Once the inflammatory factors have disappeared, ILC1 will transdifferentiate back into ILC2 and ILC3 again under the influence of IL-23 and IL-1Bèta. “This reversible plasticity is a remarkable feature of the ILC subsets”, Bernink remarks. “It shows that ILCs are highly flexible, direct responsive actors to a change in their environment. Thus they contribute to the type and the severity of an immune response. Unfortunately, this reversibility seems to be affected in COPD and Crohn's patients, who are chronicly exposed to pro-inflammatory stimuli. ILC1 even contributes to this vicious circle by its production of IFN-γ.” 

Treatment options?
Bernink has described the mechanism, but it is of course attractive to speculate about therapeutic options this plastic mechanism might offer. Bernink: “The ILCs effector function and plasticity are mainly regulated by cytokines. Action on these cytokines by for instance blocking or stimulating antibodies would therefore be an optional approach. Such an intervention would, however, normally not target ILCs specifically. The cytokines would also affect many other cell types with sometimes opposing effects as compared to the effect on certain ILC subsets.” Another option, as described by Bernink et al. As well as by also others, is the deployment of small molecules to inhibit or stimulate certain transcription factors to influence the transdifferentiation process. 

But first things first: Bernink is still busy describing the plasticity of the process: “Transdifferentiation seems to take place in a triangle; ILC1 transdifferentiates into ILC2 and ILC3 and ILC2 also can transdifferentiate to ILC3. All combinations seem to be possible. Our current studies suggest that the system is even more complex than thought before. There are probably more subsets involved and the plasticity of individual cells within the three subsets seems to vary widely. Sorting this out, which I'm determined to do, will probably keep me busy for another six months.”

Beyond that, Bernink doesn't exclude the possibility to start exploring new topics altogether. “When opportunity knocks, it is wise to consider your options. And as opportunity has knocked, I am currently considering a position.”

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