University of California San Francisco researchers recently discovered fully formed gut and skin cells in the thymus. According to their paper, which was published in Nature today, the 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 addition, the scientists discovered that Hassall's corpuscles are surrounded by tuft cells, a type of sensory cell native to the gut that detect 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 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. Intriguingly, tuft cells' sensory abilities could potentially present opportunities for medically regulating thymus function more generally, said study senior author Mark Anderson, M.D., Ph.D.
Anderson's team was specifically in interested in learning whether there might be multiple types of thymus cell involved in T cell training. In collaboration with UCSF immunologist Richard Locksley, M.D., 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. (It was previously shown that 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.)
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. "When Rich and I first saw this three years ago we were like, 'you've got to be kidding me,'" Anderson said. "Unlike the typical training cells in the thymus, the tuft cells we see there have the same physical characteristics of 'real' tuft cells in the gut. They've even got the tuft!"
The researchers showed in imaging experiments that the skin-like cells and tuft cells clump together to form Hassall's corpuscles. Though these thymic tuft cells looked just like their counterparts in the gut, molecular analyses showed that they express special proteins needed to present "self" molecules to T cells, indicating that they likely play a part in the thymus' immune curriculum.
To test the functional importance of these thymic tuft cells for a healthy immune response, the researchers genetically engineered a group of mice to lack all tuft cells, then transplanted these animals' thymuses into nude mice that lack a thymus. The transplanted thymuses began training T cells in these animals for the first time, but without the benefit of thymic tuft cells, the researchers could easily stimulate them to generate an autoimmune response against the native tuft cells of the nude mouse gut.
The team says this experiment demonstrated that thymic tuft cells play a key role in preventing autoimmunity in the gut, though further experiments are needed to clarify exactly how they contribute to T cell education. "Since the skin and the gut are two of the places where your tissues are directly exposed to the outside world, we hypothesize that Hassall's corpuscles and the surrounding tuft cells may be a second level of training that essentially simulates these critical environments for maturing T cells to test how they respond," Anderson said.