2. Academic Validation
  3. Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy

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.
Nicole L Huang 1,  Jessica G Ortega 2,  Kyleigh Kimbrell 1,  Joah Lee 1,  Lauren N Scott 3,  Esther M Peluso 4,  Sarah J Wang 1,  Ellie Y Kao 5,  Kristy Kim 1,  Jarod Olay 6,  Jaden N Nguyen 6,  Zoe Quandt 7,  Trevor E Angell 8,  Maureen A Su 6 9,  Melissa G Lechner 1
Affiliations

Affiliations

  • 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.
PMID: 40626363 DOI: 10.1172/jci.insight.188843
Abstract

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.

Keywords

Autoimmune diseases; Autoimmunity; Cancer immunotherapy; Diabetes; Oncology.

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