Every minute of every day of our lives, our immune system has to decide what to respond to, and how large the response should be. Our highly specific immune system can potentially recognize and respond to any chemical entity, which are called ‘antigens’. An antigen can be anything, from components of our own bodies, food, things we breathe in, even our clothing. Most importantly, our immune system must precisely detect parts of invading pathogens like viruses, worms, fungi and bacteria and then eliminate them. Normally our immune system is very efficient with recognition and defensive processes. However, in many diseases, the response is not enough (chronic infection, cancer), attacks our own tissues (autoimmune diseases), or is uncontrolled and causes collateral damage (sepsis). The central question of immunology is how the immune response makes the right or wrong decisions. The Murray group seeks to understand decision making in the immune system. More broadly, the complex regulation of the immune system can be used as a ‘laboratory’ to discover new biological principles. Since any component of the immune system can be transiently eliminated, transferred or genetically altered, immunologists have significant experimental advantages in dissecting cellular and biochemical pathways essential in single tissues like the brain or heart.
New advances have delineated pathways that control immune networks and how the different cell types and pathways can be manipulated. A good example is the use of immune checkpoint inhibitors in cancer therapy. Immune ‘checkpoint’ molecules like PD-1 and its ligands (PD-L1 and PD-L2), or CTLA4, are cell surface proteins that naturally provide ‘stop’ signals to T cells. Checkpoint inhibitors work by temporarily blocking the ‘stop’ signal, and allowing T cells to continue to survey tumor tissue and potentially recognize it as ‘foreign’ or damaged. In infection, these molecules are part of complex communication networks that help the immune system avoid self-reactivity once the danger of infection has passed. In cancer however, tumor cells are a type of ‘self’ and therefore can evade (in part) immune surveillance; blocking checkpoint molecules like PD-1 and CTLA4 have become very useful anti-cancer drugs and recognized by the 2018 Nobel prize in Medicine or Physiology. The PD-1 and CTLA4 are, however, only one of hundreds of intricate and complex pathways the immune system uses to regulate itself.
Information about siginficant discoveries of the Murray laboratory you find here
Current project areas
Our research focuses on the mechanisms that regulate the development and activity of the immune system and how these findings can be extended to broader biological principles. Recently, we have concentrated on the immunoregulatory events controlled by metabolism and metabolic signals. First, we are understanding how amino acid metabolism is used by the immune system as a regulatory network. All immune cells require most of the non-essential and all the essential amino acids. However, selective pressure has focused immune regulatory networks to harness metabolism of arginine and tryptophan. A related research area is to understand how immune cells detect specific amino acids and respond and adapt to low amino acid stress, which is found in almost all tissues where nutrients and oxygen become limiting. A second area builds upon our recent discoveries to understand how the inflammatory cytokine TNF controls wound healing or ‘resolving’ immunity. Anti-TNF drugs are by far the most used biologic medicines and have provided clinical benefit for millions of people with Crohn’s Disease and rheumatoid arthritis. Nevertheless, the exact mechanisms of blocking TNF remain unclear. Our recent work provides a new insight into the mechanisms of these drugs and how their mechanisms intersect with the metabolic pathways that govern immune activity.