Understanding how Tim-3 regulates inflammasome formation in dendritic cells to shape T cell responses in autoimmunity and cancer

Checkpoint molecules such as Tim-3 can be leveraged to manipulate T cell responses in cancer and autoimmunity.

Tim-3 specifically is considered to affect T cells directly, but recent data demonstrate that Tim-3 primarily acts through dendritic cells, in particular by affecting the inflammasome.

Understanding the exact mechanisms by which Tim-3 mediates its effects is critical given ongoing clinical trials in cancer and autoimmunity targeting this pathway.

This proposal aims to investigate how Tim-3 modulates dendritic cells and inflammasome activation, and how this in turn impacts T cell responses in autoimmunity and anti-tumor immunity.

We will use novel conditional Tim-3 gain- and loss-of-function mice to dissect the effects of Tim-3 on dendritic cells and T cell responses in pre-clinical models of autoimmunity and cancer.

Using these mice, we will also pinpoint the exact molecular mechanism by which Tim-3 inhibits inflammasome activation in a whole genome lentiviral sgRNA CRISPR screen. Finally, we will also use these mice to investigate Tim-3 mediated resistance to Pd-1 checkpoint blockade. The project will run for 3-years starting Jan. 2022.

The first two years in the Kuchroo lab Harvard Medical School; the last year in the Coquet lab at Karolinska Institute.

Both labs are leading in the in vivo study of immune responses, providing access to state-of-the-art animal facilities, unique animal strains, and cutting-edge methodologies to dissect immune responses.