Clonally expanded, thyrotoxic effector CD8⁺ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis

Area of Science:

• Immunology
• Oncology
• Endocrinology

Background:

• Immune checkpoint inhibitors (ICIs) are vital cancer treatments but can cause significant autoimmune toxicity, known as immune-related adverse events (IRAEs).
• Thyroid dysfunction, specifically ICI-induced thyroiditis, is a common IRAE, posing a challenge to patient management and treatment expansion.
• Previous studies on IRAEs primarily analyzed peripheral blood, limiting insights into tissue-specific immune responses.

Purpose of the Study:

• To investigate the immunopathogenesis of ICI-induced thyroiditis by directly analyzing affected thyroid tissue.
• To compare immune cell infiltrates in ICI-thyroiditis with spontaneous autoimmune Hashimoto's thyroiditis (HT) and healthy thyroid tissue.
• To identify specific immune cells and molecular pathways driving ICI-related thyroid autoimmunity.

Main Methods:

• Acquisition and analysis of thyroid specimens from patients with ICI-thyroiditis, Hashimoto's thyroiditis (HT), and healthy controls.
• Single-cell RNA sequencing to characterize immune cell populations and their gene expression profiles.
• In vivo validation using a mouse model of IRAEs, including genetic deletion of IL-21 signaling.

Main Results:

• A distinct population of clonally expanded, thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells was identified in ICI-thyroiditis, absent in HT and healthy controls.
• Interleukin-21 (IL-21), secreted by T follicular helper (T_FH) and T peripheral helper (T_PH) cells, was found to drive the activation and cytotoxic function of these CD8+ T cells.
• IL-21 promoted CD8+ T cell expression of interferon-γ (IFN-γ), granzyme B, and CXCR6, conferring thyrotoxic capacity. Genetic deletion of IL-21 signaling protected mice from thyroid immune infiltration.

Conclusions:

• Thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells are a hallmark of ICI-induced thyroiditis.
• IL-21 is a critical cytokine mediating the thyrotoxic effector function of these T cells.
• These findings reveal key mechanisms of ICI-induced thyroid autoimmunity and highlight IL-21 and specific CD8+ T cells as potential therapeutic targets.