Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy
Nicole L. Huang, … , Maureen A. Su, Melissa G. Lechner
Nicole L. Huang, … , Maureen A. Su, Melissa G. Lechner
Published July 8, 2025
Citation Information: JCI Insight. 2025;10(13):e188843. https://doi.org/10.1172/jci.insight.188843.
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Research Article Oncology

Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy

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.

Authors

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

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Figure 2

IL-21 and IFN-γ are key cytokine mediators of ICI-T1DM.

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IL-21 and IFN-γ are key cytokine mediators of ICI-T1DM. (A) Schematic of...
(A) Schematic of cytokine production by Tfh cells. (B) Incidence curve for ICI-T1DM in anti–PD-1 treated NOD WT and NOD.Il21r–/– (IL-21R KO) mice. WT, Iso (6 males, 7 females); IL-21R–KO, Iso (11 males); IL-21R–KO, anti–PD-1 (8 males, 2 females). (C) Incidence curve for ICI-T1DM in ICI-treated NOD WT and NOD.IFN-γ–/– (IFN-γ–KO) mice during anti–PD-1 treatment. WT, Iso (6 males, 7 females); IFN-γ–KO, Iso (6 males, 3 females); IFN-γ–KO, anti–PD-1 (6 males, 7 females), WT, anti–PD-1 (3 males, 4 females). (D) Representative H&E-stained pancreas histology sections of Iso- or anti–PD-1–treated WT, IL-21R–KO, or IFN-γ–KO mice (original magnification, 100×). Arrow indicates an islet of Langerhans. (E) Insulitis index determined by histologic analyses of pancreas islet histology across indicated treatment conditions. WT, Iso (5 males, 10 females); WT, anti–PD-1 (6 males, 10 females); IL-21R–KO, anti–PD-1 (4 males, 1 female); IFN-γ–KO, anti–PD-1 (5 males, 5 females). (F) Quantification of CD4+ T, CD8+ T, and B cells from anti–PD-1–treated WT (2 males, 2 females), IL-21R–KO (2 males, 1 female), and IFN-γ–KO (5 males, 4 females) mice or Iso WT (1 male, 3 females), via multi-immunofluorescence staining. Comparisons by log-rank test (B and C), Fisher’s exact test (E), or Brown-Forsythe ANOVA with Welch’s pairwise comparison test (F). **P < 0.01, ***P < 0.001, ****P < 0.0001.