Polyfunctional IL-21+ IFNG+ T follicular helper cells contribute to checkpoint inhibitor diabetes mellitus and can be targeted by JAK inhibitor therapy

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 beta-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. Here, we identify expansion CD4⁺ T follicular helper (Tfh) cells expressing interleukin 21 (IL-21) and interferon gamma (IFNG) as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFNG are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFNG 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.