A research team from the Salk Institue has found a protein that controls both the survival and function of Tregs. This activity has implications that could help improve cancer immunotherapy as well as developing better treatments for autoimmune diseases such as rheumatoid arthritis and type 1 diabetes. The work can be seen in this week's Proceedings of the National Academy of Sciences.
Tregs act as the traffic cops of the immune system and direct the other immune cells when to stop and go. With faulty Tregs, immune cells don't have a regulator to help them direct their activity.
This Salk Institute team studies a protein called Lbk1 (liver kinase B1), which is known to play a role in cell metabolism. However, in this study, they found that Lbk1 plays a role in the immune response of Tregs.
The team used mice that had Lkb1 gene knocked out in their Treg cells and saw that their animals were showing signs of autoimmune disease. With closer examination, they saw that the metabolic machinery in the Tregs was disrupted. These cells had defective mitochondria and were unable to power themselves.
"Through these observations, we determined that the Lkb1 pathway is responsible for supplying Tregs with energy," says Ye Zheng, an associate professor in Salk's Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis. "Without it, Tregs don't have enough fuel to function."
"It turns out that Tregs require a lot of energy to do their job, which is essentially to prevent other kinds of T cells from attacking the body," adds Michael Downes, a Salk senior scientist. "This is something that wasn't previously recognized, and it's an important discovery."
The researchers say that Lkb1 itself will be hard to target, so they are looking at molecules downstream in the signaling pathway that could be altered with drugs. Their plan is to focus on the development of these drugs for now.
Image: Skin samples from mice whose regulatory immune cells (Tregs) lack the Lkb1 protein (bottom) are under attack from other immune cells (purple dots) compared to normal mice whose Tregs have the Lkb1 protein (top). Image courtesy of the Salk Institute.