Defining how phospholipid signaling networks control Th17 differentiation and effector function
Autoimmune diseases represent a substantial public health burden, affecting over 7% of the population (23.5
million people) and incurring costs upward of 1 billion dollars per year in the US alone. The adaptive immune
system generates an autoreactive response when self-tolerance mechanisms are broken. In this autoreactive
cascade, proinflammatory CD4+ T cell populations develop, damage host tissues, and cause disease pathology.
In autoimmune diseases, including MS and rheumatoid arthritis, the ratio of proinflammatory Th17 to regulatory
T cells (Treg) skews towards elevated Th17. Recent work suggests that reestablishing a healthy Treg/Th17
balance has therapeutic potential for autoimmune diseases. The required cytokines and transcription factors that
program Treg versus Th17 differentiation are well established. Much less is known about the intracellular
signaling networks that drive Th17 differentiation. Identifying signaling proteins essential for Th17s and
dispensable for Tregs represent “vulnerable liabilities” to target with small molecule inhibitors. In our recent
publication, we systematically apply phosphoproteomics to profile kinase signaling during Treg versus Th17
differentiation. Our foundational phosphoproteomics datasets identify many new signaling circuits representing
new basic T cell biology and provide possible targets for drug therapies to block proinflammatory Th17 cells
while maintaining Treg function. We determined that phosphatidylinositol kinase, PIKFYVE, was differentially
regulated during Treg versus Th17 differentiation. Our biochemical analysis reveals that PI(3,5)P2 synthesis, the
product of PIKFYVE, is upregulated explicitly during Th17 differentiation, arguing that PI(3,5)P2 is an essential
signaling molecule specific to the Th17 differentiation program. Blocking PIKFYVE diminished Th17
differentiation and disease in the experimental autoimmune encephalomyelitis (EAE) model. Our findings serve
as a solid rationale for mechanistically defining how PIKFYVE/PI(3,5)P2 promotes Th17 differentiation and EAE
disease. Inhibiting PIKFYVE is as effective at diminishing EAE disease as some FDA-approved therapeutics for
MS, establishing PIKFYVE/PI(3,5)P2 as a high impact target. Based on our published and preliminary data, we
propose the central hypothesis that PIKFYVE/PI(3,5)P2 is required for Th17 differentiation and EAE pathology.
We will determine how PIKFYVE/PI(3,5)P2 regulates immune cell function in the EAE model. This analysis will
determine if genetic deletion of PIKFYVE in CD4+ T cells downmodulates Th17 differentiation in the EAE model
and reduces neuroinflammation. We will also determine if blocking PIKFYVE diminishes effector T cell function.
Additionally, will determine the molecular mechanisms by which PIKFYVE/PI(3,5)P2 regulates Th17
differentiation. This analysis will identify how PIKFYVE regulates kinase networks and transcriptional programs
to support Th17 differentiation. Completing this work will define the importance of PIKFYVE in T cell biology and
inform therapeutic strategies for autoimmune diseases caused by Th17 cells.
