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

ABSTRACT: Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto's thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6⁺ CD8⁺ T cells (effector CD8⁺ T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (T_FH) and T peripheral helper (T_PH) cells, as a driver of these thyrotoxic effector CD8⁺ T cells. In the presence of IL-21, human CD8⁺ T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-γ (IFN-γ) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.

SUBMITTER: Lechner MG

PROVIDER: S-EPMC10227862 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Clonally expanded, thyrotoxic effector CD8<sup>+</sup> T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis.

Lechner Melissa G MG Zhou Zikang Z Hoang Aline T AT Huang Nicole N Ortega Jessica J Scott Lauren N LN Chen Ho-Chung HC Patel Anushi Y AY Yakhshi-Tafti Rana R Kim Kristy K Hugo Willy W Famini Pouyan P Drakaki Alexandra A Ribas Antoni A Angell Trevor E TE Su Maureen A MA

Science translational medicine 20230517 696

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and ...[more]

PMID: 37196065

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Project description:Alzheimer’s Disease (AD) is the most common cause of age-related dementia and the sixth leading cause of death in the United States. AD neuropathology is primarily characterized by the accumulation of extracellular beta-amyloid (Aβ) plaques and intraneuronal neurofibrillary tau tangles. In addition to these hallmark AD pathologies, many other important pathological changes occur in the brains of AD patients, including synaptic and neuronal loss and neuroinflammation. Most recently, genome-wide association studies (GWAS) have provided substantial new evidence that immune dysfunction may contribute to the development and progression of AD. To date over 60 GWAS loci have been identified and almost two thirds of these genes are highly expressed in microglia, the resident innate immune cell of the brain. These genetic discoveries have in turn inspired many new studies of microglial biology and the role of these cells in AD. In contrast, the role of the adaptive immunity in AD remains understudied, despite evidence that many of AD risk genes are also highly expressed in T and B cells. To investigate the role of T cell infiltration in AD, we examined T cells from immune-deficient AD mice via bone marrow transplantation studies using flow cytometry and immunohistochemistry; and from immune-intact transgenic AD model mice using flow cytometry, immunohistochemistry, and single-cell RNA sequencing. Our experiments demonstrate that multiple T cell subtypes infiltrate the AD brain, and that effector memory CD8 T cells are specifically enriched in response to Aβ pathology or a combination of Aβ and tau pathologies. Single-cell sequencing analysis revealed high expression of over 40 AD risk genes between several T cell sub-populations, implying a need for more research of these T cell phenotypes in AD development. Additionally, T-cell receptor (TCR) sequencing revealed increased clonal expansion of T cells from mice that developed Aβ pathology or Aβ and tau pathology, suggesting amyloid-driven recruitment and clonal expansion of T cells in these mice. Ultimately, this study demonstrates the crucial importance of investigating the role of T cells in AD and provides a guide for future experiments to continue to enhance our understanding of AD immunology.

Dataset Information

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

Publications

Clonally expanded, thyrotoxic effector CD8<sup>+</sup> T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis.

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Dataset Information

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

Publications

Clonally expanded, thyrotoxic effector CD8<sup>+</sup> T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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