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Clonally expanded CD38^hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.

ABSTRACT: Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38^hiCD127^- CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38^hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38^hiCD127^- T cells, which were frequently bound by the therapeutic anti-PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.

SUBMITTER: Wang R

PROVIDER: S-EPMC10557056 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Clonally expanded CD38<sup>hi</sup> cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.

Wang Runci R Singaraju Anvita A Marks Kathryne E KE Shakib Lorien L Dunlap Garrett G Adejoorin Ifeoluwakiisi I Greisen Stinne R SR Chen Lin L Tirpack Aidan K AK Aude Carlos C Fein Miriam R MR Todd Derrick J DJ MacFarlane Lindsey L Goodman Susan M SM DiCarlo Edward F EF Massarotti Elena M EM Sparks Jeffrey A JA Jonsson A Helena AH Brenner Michael B MB Postow Michael A MA Chan Karmela K KK Bass Anne R AR Donlin Laura T LT Rao Deepak A DA

Science immunology 20230728 85

Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthrit ...[more]

PMID: 37506196

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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.

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Dataset Information

Clonally expanded CD38^hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.

Publications

Clonally expanded CD38<sup>hi</sup> cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.

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Dataset Information

Clonally expanded CD38hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.

Publications

Clonally expanded CD38<sup>hi</sup> cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Clonally expanded CD38^hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.