UC San Francisco researchers were recently surprised to discover fully formed gut and skin cells in the thymus, a lemon-sized organ that sits in front of the heart and is responsible for training the T cells of the immune system not to attack the body's tissues.

The finding, based on studies conducted on mice, could lead to a better understanding of the drivers of autoimmune problems in humans, the authors say. The cells in the medulla region of the thymus have a straightforward task: they are programmed to randomly display bouquets of proteins characteristic of various bodily tissues to "train" newborn T cells, the immune cells responsible for defending the body against invasive pathogens.

If immature T cells respond aggressively to these "friendly" proteins, the thymus either eliminates them or retrains them as peacekeeping Treg ("tee-reg") cells that can suppress inflammation in the body's tissues. Bad quality control in the thymus can lead to autoimmune diseases such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis.

The immune cells

Now, in a study published July 18, 2018 in Nature, researchers at the Diabetes Center at UCSF have discovered that tiny clusters of cells in the thymus called Hassall's corpuscles, the function of which has been a mystery to science for over 150 years—consist of much more complex epithelial and sensory cells, akin to mature cells of the skin and the gut.

In particular, the scientists discovered that Hassall's corpuscles are surrounded by tuft cells, a type of sensory cell native to the gut which detects invasive parasites in the mouse gut by "tasting" them through chemical detectors on the finger-like cilia that make up the cells' characteristic tufts.

The new study showed that these newly discovered sensory cells in the thymus play an important role in training the developing immune system of mice, suggesting that thymic tuft cells could also play a role in autoimmune problems such as inflammatory bowel disease in humans.

Intriguingly, tuft cells' sensory abilities could potentially present opportunities for medically regulating thymus function more generally, said senior study author Mark Anderson, MD.

Anderson is a physician-scientist who has spent more than a decade studying the thymus's immune-training "curriculum" in the lab to develop new treatments for autoimmune conditions such as type 1 diabetes.

His team has previously shown that a gene called AIRE is responsible for making cells in the medulla region of the thymus produce their random handful of "self" proteins to test newborn T cells for autoimmune tendencies.

In the new study, Anderson's team was interested in learning whether there might be multiple types of thymus cell involved in T cell training. In collaboration with pioneering UCSF immunologist Richard Locksley, MD, the researchers developed a new technique for tracing the genetic development of thousands of individual AIRE expressing cells, and to their surprise, they discovered two subsets of cells that consistently turned off AIRE and began expressing two very different genetic programs.

One group of cells appeared to differentiate into epithelial cells akin to those that form the outer layer of the skin, and the other group began expressing markers of a type of sensory cell residing in the gut called "tuft" cells.