Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy
- JCI Insight. 2025 Jul 8;10(13):e188843. doi: 10.1172/jci.insight.188843.
- 1. Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, California, USA.
- 2. UCSF Medical School, San Francisco, California, USA.
- 3. University of Kansas Medical School, Kansas City, Kansas, USA.
- 4. UCLA/California Institute of Technology Medical Scientist Training Program, UCLA David Geffen School of Medicine, Los Angeles, California, USA.
- 5. California State Polytechnic University, Pomona, California, USA.
- 6. Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, California, USA.
- 7. Division of Endocrinology and Metabolism, UCSF Medical School, San Francisco, California, USA.
- 8. Division of Endocrinology and Diabetes, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
- 9. Division of Pediatric Endocrinology, UCLA David Geffen School of Medicine; Los Angeles, California, USA.
Immune checkpoint inhibitors (ICI) have revolutionized Cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, Cancer treatment interruption, and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic β-islet cell destruction leading to hyperglycemia and life-long Insulin dependence. While prior reports have focused on CD8+ T cells, the role for CD4+ T cells in ICI-T1DM is less understood. We identify expansion of CD4+ T follicular helper (Tfh) cells expressing IL-21 and IFN-γ as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFN-γ are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFN-γ both signal through JAK/STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust in vivo protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4+ Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.