Associated Project - Mufazalov
The role of cytokine receptors in the maintenance of Treg cell identity in inflammation
Background
Treg cells are critical players in keeping inflammatory responses in check. Their ability to survive and mediate immune suppression in conditions with high levels of pro-inflammatory cytokines is a key feature that remains poorly understood. Deciphering the natural mechanisms by which Treg cells can persist in such toxic environments is critical for the development of potent Treg cell-based therapies. Indeed, such therapy could be improved by stabilizing the expression or, in opposite, by preventing the expression of relevant cytokine receptors on Treg cells. This approach is likely to improve Treg functionality and stability at the site of the targeted inflammation.
We hypothesize that the tuning of cytokine receptors is crucial for maintenance of Treg cell identity in inflammation, and Treg cell-based therapies will benefit from adjusting the cytokine receptor profile on Treg cells depending on the type of inflammation.
Strategy
To identify cytokine receptors on Treg cells which are critical for Treg cell fitness in inflammation we utilize preclinical in vivo models. Our pioneering model is a mouse strain with Cre-mediated interleukin-6 (IL-6) overexpression, in which we selectively activate IL-6 production by a desired cell type. In these mice, high levels of IL-6 trigger a local or systemic inflammation with the induction of several other cytokines. In addition, we complement this model with Treg-specific deficiency in cytokine receptors of several inflammatory pathways such as IL-1, IL-6, IL-17A or TNF. We use our model to test if the absence of one or another signaling receptor will lead to improved Treg cell fitness in vivo.