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

## TL;DR

A new type of immune cell drives diabetes caused by cancer immunotherapy, and this can be treated with JAK inhibitors.

## Contribution

Identifies CD4+ T follicular helper cells as key drivers of ICI-induced diabetes and proposes JAK inhibitors as a treatment.

## Key findings

- CD4+ T follicular helper cells expressing IL-21 and IFN-γ are central to ICI-induced diabetes.
- JAK inhibitors protect against ICI-induced diabetes in mice and reduce Tfh cell differentiation in patients.

## 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.

Multifunctional IL-21+ IFNg+ CD4+ T follicular helper cells are key drivers of checkpoint immunotherapy-induced autoimmune diabetes that can be targeted with JAK inhibitor therapy.