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- Title
CD4<sup>+</sup> T cells are essential for the development of destructive thyroiditis induced by anti–PD-1 antibody in thyroglobulin-immunized mice.
- Authors
Yasuda, Yoshinori; Iwama, Shintaro; Sugiyama, Daisuke; Okuji, Takayuki; Kobayashi, Tomoko; Ito, Masaaki; Okada, Norio; Enomoto, Atsushi; Ito, Sachiko; Yan, Yue; Sugiyama, Mariko; Onoue, Takeshi; Tsunekawa, Taku; Ito, Yoshihiro; Takagi, Hiroshi; Hagiwara, Daisuke; Goto, Motomitsu; Suga, Hidetaka; Banno, Ryoichi; Takahashi, Masahide
- Abstract
Adverse events in the thyroid: Anti–programmed cell death–1 (PD-1) antibody blockade has revolutionized cancer treatment by enhancing immune responses against tumors. However, anti–PD-1 treatment can also induce immune-related adverse events by promoting autoreactive immune responses. In this study, Yasuda et al. investigated the immune cell type responsible for promoting destructive thyroiditis, a common adverse event observed in patients treated with anti–PD-1 antibody. The authors found that CD4+ T cells are required for the onset of destructive thyroiditis in a mouse model, which was supported by analysis of circulating CD4+ T cells isolated from patients. These results suggest that CD4+ T cells may mediate destructive thyroiditis in patients with cancer after anti–PD-1 treatment. Immune-related adverse events induced by anti–programmed cell death–1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by depleting CD8+ T cells. The frequencies of central and effector memory CD4+ T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4+ T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4+ T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4+ T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4+ T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.
- Subjects
MONONUCLEAR leukocytes; CYTOTOXIC T cells; DRUG side effects; THYROIDITIS; LABORATORY mice; MAJOR histocompatibility complex; PROGRAMMED cell death 1 receptors; T cells
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 593, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abb7495