Saskia Hemmers

IL-1R family members as integrators of tissue states in neuroinflammation

The Hemmers lab routinely uses reverse genetics and genetic fate-mapping approaches in mice. More specifically, we have generated novel conditional knockout alleles for various receptors of the IL-1R family associated with acute tissue damage and inflammation (IL-18R, IL-33R, DKO -IL-18R/IL-33R) to study their contribution to neuroinflammation. In a recent study, we highlighted the unique role of IL-33R expressed by regulatory T cells in dampening inflammation by keeping pathogenic TCRgd⁺ T cells in check. We are currently expanding our exploration beyond T cells to include glial cell populations (in collaboration with the Eroglu lab) and will also explore models of neuropathic pain.

In a separate line of research, we have exciting preliminary data that suggests a genetic interaction of loss of the decoy receptor for IL-1 (IL-1R2) with biological sex. More specifically, we have observed disease exacerbation in a mouse model of autoimmune demyelination in the CNS upon loss of IL-1R2 in the myeloid compartment, but this was only seen in female mice. While exploring the mechanistic basis of these findings, we have also set out to ask more generally how biological sex affects immune cells at steady-state. To this end, we have designed a scRNA-sequencing approach utilizing Cite-seq and bone marrow chimeras to explore the cell-extrinsic and cell-intrinsic effects of biological sex on immune cells in spleen, lung, and liver.

Imprinting of perinatal origins on T cells

Our adult immune system is comprised of a mixture of cells with distinct developmental origins: some cells originated from fetal tissues, some emerged right after birth, and some were generated in the adult. We describe this phenomenon as layered immunity. One hallmark of such a layered immune system is that these successively arising cells are functionally distinct. The relative contribution of cells from each developmental wave likely varies between individuals and will affect the quality of the immune system. It is interesting to speculate that infection during early life will have a significant impact on the layered composition of the adult immune system. However, it is not trivial to assess the relative contributions from various developmental origins as we lack specific markers to identify those cells. Our research will use genetic tools in mice to timestamp cells to mark their developmental origin so that we can study their function and relative contributions to the adult immune system. Moreover, this will give us a benchmark to investigate how infections might change the composition of our layered immune system and how these shifts affect our immune status in the future.