October 30, 2025 | By Asher Jones
Th17 cells are a type of helper T cell that stimulate inflammatory responses to fend off bacterial and fungal infections. But they have a dark side, too: When Th17s become pathogenic, they can drive inflammatory and autoimmune diseases such as rheumatoid arthritis, lupus, and multiple sclerosis (MS).
In a new Journal of Neuroinflammation study, University of Pittsburgh immunologists gained new insights into the processes that drive Th17 cells to delinquency and lead to autoimmune neuroinflammation in a mouse model of MS.
“We started out with a simple question: What makes pathogenic Th17 cells different from other T cells, and could we target them specifically to treat disease?” said senior author William Hawse, assistant professor of immunology at the Pitt School of Medicine.
Previously, Hawse and his team found that a protein called PIKFYVE is essential for Th17's path to pathogenicity. PIKFYVE is an enzyme that switches on a transcription factor called STAT3 by adding phosphate groups, enabling it to activate other proteins and enhance expression of certain genes. When the researchers inhibited or deleted PIKFYVE in a mouse model of MS, symptoms including neuroinflammation greatly improved.
To learn more about how PIKFYVE causes MS symptoms, Hawse, co-first authors Douglas Prado, a postdoc in Hawse’s lab, and Achyudhan Kutuva, a graduate student in the joint Pitt–Carnegie Mellon University Program in Computational Biology, and their team looked at a relatively unexplored role of PIKFYVE that involves phosphorylating a specific region of STAT3 — a serine amino acid at position 727 of the protein chain.
Using the same model of MS, the researchers generated mice with a point mutation in the genetic code of STAT3 that switches serine for alanine, preventing phosphorylation at this location.
Then, they took T cells from wild-type or genetically modified mice and transferred them into immunodeficient mice. Animals that received the genetically engineered T cells had much milder disease than those that received wild-type T cells, including less neuroinflammation and reduced loss of the spinal cord’s myelin sheath. These findings suggested th
at phosphorylation of serine 727 is important for the development of MS symptoms in mice.
“Myelin is like insulation for the spinal cord,” said Hawse. “In our mouse model of MS, this insulation disintegrates, producing holes that look like Swiss cheese. But when we replaced serine 727 with alanine so it could no longer be phosphorylated, myelin was protected.”
Additional experiments showed that phosphorylation of serine 727 promotes interactions between STAT3 and other genetic regulators, ultimately altering gene expression patterns that drive disease.
“Changing a single amino acid had a profound effect on disease in this model of MS,” said Hawse. “Because serine 727 is conserved in human STAT3, we think that selectively blocking phosphorylation at this site could offer therapeutic benefits.”
The next step is investigating whether these findings hold true in humans by analyzing samples from MS patients. They are also working on developing small molecule inhibitors of PIKFYVE to prevent phosphorylation of serine 727.
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Image 1: Members of the Hawse Lab and authors on the study. From left to right: Achyudhan Katuva, Richard Cattley, Andreza Buzolin Sonego, Elana Im and Douglas Prado.
Image 2: In mice that received wild-type T cells (left), the protective myelin sheath (stained blue) of the spinal cord deteriorates, producing Swiss cheese–like holes. The myelin sheath is protected in mice that received genetically engineered T cells lacking serine 727 (right). [Credit: Prado et al. 2025, J. Neuroinflammation]