Regulation Of Immune Responses

Our laboratory is interested in genes and pathways that regulate immune signaling and understanding how changes in these mechanisms can lead to autoimmune diseases such as Systemic Lupus Erythematosus (SLE) or Inflammatory Bowel Disease (IBD). We use genetics, biochemistry and cell biology approaches to understand how these pathways function in different immune cell types, and in vivo models to work out how these mechanisms contribute to autoimmunity.

A long term interest of the lab is in the co-operation between a family of cell surface receptors, the alpha-v integrins and the cytokine TGF-beta. TGF-beta is critical for regulation of the immune system, and signals to multiple immune cell types to dampen immune responses and resolve inflammation.

TGF-beta is mostly synthesized in an inactive form and must be released before it can signal. The lab has shown that dendritic cells (DCs) and macrophages can bind and activate TGF-beta through alpha-v beta 8 integrin, leading to TGF-beta signaling to other immune cell types including T cells. Currently, the lab is working to understand how DCs come to express alpha-v beta-8, how this triggers TGF-beta activation, and whether targeting this process may provide a therapeutic strategy for IBD and Multiple Sclerosis (MS), as well as other diseases such as cancer.

Recently we have identified a new role for genes involved in autophagy in regulating immune signaling. Autophagy is the process by which cells ‘eat themselves’ during starvation or in response to stress or cellular damage. We have found that some components of the autophagy pathway are triggered when immune cells are activated through toll-like receptors (TLRs), and reduce TLR signaling. TLRs recognize specific macromolecules present in pathogens, such as bacterial cell walls or viral genomes, and trigger production of inflammatory cytokines to induce immune responses. However, components of our own cells can also trigger TLR signaling and this is thought to contribute to autoimmune diseases such as SLE.

We think that this autophagy pathway exists to prevent overactive TLR signaling to self-derived ligands and we have found that disruption of this pathway contributes to autoimmunity. Current work in the lab investigates how this pathway works in B cells, plasmacytoid DCs and macrophages to control autoimmune responses, and how genetic variation in autophagy components contribute to SLE in patients.