The Revelation of Regulatory T Cells and the Role of Foxp3
The story of regulatory T cells (Tregs) – the immune system’s internal brakes – began with a puzzling genetic mutation in mice. In the 1980s, researchers observed a severe autoimmune condition in a strain of mice dubbed “scurfy.” These mice suffered from a rapidly fatal inflammatory disease, prompting a search for the underlying genetic cause.
In the 1990s, pinpointing the responsible gene proved challenging. The mutation was eventually located to a region on the X chromosome containing 20 potential candidate genes. After painstaking analysis, a small two-base pair insertion was identified in the final gene examined. This mutation disrupted the gene’s coding sequence,resulting in a non-functional protein. The researchers, Michael Brunkow and David Ramsdell, classified the gene as a member of the forkhead/winged-helix family and named it Foxp3.
Confirmation of Foxp3’s role came thru genetic rescue experiments. Introducing a normal Foxp3 gene into scurfy mice in five autonomous lines successfully prevented the development of the autoimmune disease, definitively linking the mutated gene to the condition.Further examination revealed a striking parallel in humans: a similar, often fatal autoimmune disorder called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) was also caused by mutations in the human Foxp3 gene.Brunkow and Ramsdell published these findings in 2001, establishing a clear genetic link between Foxp3 and immune dysregulation in both mice and humans.
Meanwhile, in Japan, immunologist Tasuku Honjo and his team had been independently studying a distinct population of T cells that suppressed immune responses. Over the following two years, they discovered that Foxp3 was specifically activated within these suppressor T cells, later termed regulatory T cells. Crucially, they demonstrated that forcing Foxp3 activation in conventional T helper cells could transform them into regulatory T cells.
These findings revealed Foxp3 as the master regulator of Tregs. The Foxp3 protein doesn’t act alone; it controls a network of genes that collectively equip T cells with the ability to dampen autoimmune reactions and moderate immune responses after infections have been cleared.
The discovery of Tregs and the central role of Foxp3 has revolutionized our understanding of immune tolerance. Current research focuses on harnessing the power of these cells for therapeutic benefit. Scientists are exploring strategies to disable Tregs’ protective effect on cancerous tumors, engineer Tregs to treat autoimmune diseases, and recruit them to prevent rejection of transplanted organs and tissues. The Nobel committee recognized this groundbreaking work as having “conferred the greatest benefit to humankind” by providing fundamental knowledge of how our immune systems function.
