CD4 ⁺ T cells are essential for the development of destructive thyroiditis induced by anti–PD-1 antibody in thyroglobulin-immunized mice

Abstract

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.

Immune-checkpoint inhibitors: long-term implications of toxicity

“…Notably, distinct cell types are implicated as dominant cellular populations and critical drivers in different preclinical models and biopsy samples obtained from affected tissues. For example, tissue-resident memory CD8 + T cells were the most abundant cell type in colon biopsy samples obtained from a cohort of patients with ICI-induced colitis, while cytotoxic activated memory CD4 + T cells were most prevalent in the brain of one patient with fatal encephalitis 49 , 50 , 52 , 53 . Targeted inhibition of particular cytokines, such as IL-6, could provide a method for uncoupling antitumour from antihost immune responses in preclinical models 54 , 55 .…”

Inborn Errors of Immunity and Their Phenocopies: CTLA4 and PD-1

“…Severe hypothyroidism or hyperthyroidism occurs in less than 1% (28,98,(101)(102)(103)(104)(105). Interestingly, individuals with pre-existing anti-thyroid autoantibodies are significantly more susceptible to thyroid IRAEs induced by PD-1 inhibitor (119,120). T1D and adrenal insufficiency have been observed in about 1% of patients with pembrolizumab treatment (28, 101, 104) (Table 2).…”

“…Furthermore, thyroid infiltration of PD-1 + T cells is observed in sporadic Graves' disease (123), and a mouse thyroiditis model induced by thyroglobulin immunization is exaggerated by anti-PD-1 treatment, which is prevented bydeletion of CD4 + T cells. In this model, thyroid infiltrating CD4 + T cells acquire cytotoxic features and potentially kill thyrocytes via specific recognition of thyroglobulin antigen (120).…”

Immune checkpoint inhibitor-related endocrinopathies

“…[ 6 ] Furthermore, in rodent models, it was revealed that cytotoxic memory CD4 + T cell was activated by PD-1 antibody and led to anti-PD-1 therapy-related destructive thyroiditis. [ 7 ] The pituitary glands at autopsy of six patients with CTLA-4 blockade-induced hypophysitis proved the expression of CTLA-4 and extensive destruction after immune reactions. [ 8 ] Another study proved that treatment with anti-CTLA-4 antibody precipitated pituitary cells’ destruction via classic complement pathway.…”