Scientists discovered how a gene mutation affects T-cell function to promote immune disorders and then tested a treatment based on the discovery—successfully fixing donated immune cells from a 16-year-old boy with an abnormally low level of white blood cells called lymphopenia.

Cincinnati Children’s researchers report their findings in Nature Communications. The discovery centers on mutation of the gene Gimap5, which is important to the healthy formation and function of CD4+ T cells, one of the immune system’s super soldiers against infection and disease.

Gimap5, the protein associated with the Gimap5 gene, is important because it regulates a protein that inactivates an enzyme called GSK3β, researchers said. If GSK3β isn’t inactivated, it causes DNA damage in T cells that are expanding, causing the cells to not survive or function correctly. In mice and human blood cells, the researchers tested drugs that inhibit GSK3β, improving immune system function in mice and restoring normal T-cell function in the human cells.

GSK3 inhibitors already are used to treat other diseases like Alzheimer’s, mood disorders, and diabetes mellitus.

“Our data suggest GSK3 inhibitors will improve T-cell survival and function and may prevent or correct immune-related disorders in people with Gimap5 loss-of-function mutations,” said Kasper Hoebe, PhD, Division of Immunobiology. “Therapeutically targeting this pathway may be relevant for treating people with Gimap5 mutations linked to autoimmunity in type 1 diabetes, systemic lupus erythematosus, or asthma.”

Hoebe led the study, together with Andrew Patterson, a PhD student in Hoebe’s lab, and Jack Bleesing, MD, PhD, in the Division of Bone Marrow Transplantation and Immune Deficiency.

Immune system disorders lead to abnormally low immune activity (deficiency) or overactivity (autoimmunity). Immune deficiency diseases decrease the body's ability to fight infection, while autoimmunity prompts the body to attack its own tissues. Both are common causes of illness, and malfunctioning T cells are linked to both.