Clonally expanded CD38hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis
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ABSTRACT:
PROVIDER: PRJNA846154 | ENA |
REPOSITORIES: ENA
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Project description:Immune checkpoint inhibitor (ICI) therapies have improved outcomes for advanced malignancies by activating T cell responses, yet often also elicit harmful autoimmune reactions. The T cell mechanisms mediating these iatrogenic autoimmune events remain unclear. Here we focused on ICI-induced inflammatory arthritis (ICI-arthritis), which can clinically present indistinguishable from rheumatoid arthritis (RA). Compared to autoimmune RA and psoriatic arthritis (PsA), we found ICI-arthritis joints contained an expanded CD38hiCD127- CD8 T cell subset that displays cytotoxic, effector, and interferon (IFN) response signatures. Synovial T cells exposed to Type I IFN, more so than IFN-γ, induced the CD38hi cytotoxic phenotype. Single cell transcriptomic and T cell repertoire (TCR) analyses indicated the abundant CD38hi CD8 T cells resulted from local proliferation of a limited number of clones. The CD38hi phenotype was distinct from dysfunctional T cells and clonally most related to a TCF7+ memory population. Comparing CD8 T cells from both knees in a patient demonstrated considerable sharing of the CD38hi expanded TCR clonotypes. Further, expanded TCR clonotypes from the joints were detected in the circulation, and together with higher frequencies of circulating CD38hi CD8 T cells, represent potential biomarkers for irAEs. These results define a distinct CD8 T cell subset in humans that is activated by ICI therapy and mediates tissue-specific autoimmunity.
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Project description: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 CD38hiCD127- 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 CD38hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38hiCD127- 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.
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2019-11-04 | GSE134576 | GEO
Project description:Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which neuroinflammation plays a critical function. Recurring viral infections and loss of immune competence increase risk for developing AD, yet the cellular and molecular mechanisms driving these immune changes are unknown. Here we performed mass cytometry of peripheral blood mononuclear cells and detected an immunologic signature of AD characterized by increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. CD8+ TEMRA cells were negatively associated with cognition and single cell RNA sequencing revealed their cytotoxic effector function. Strikingly, we discovered identical, shared T cell receptors (TCRs) of clonally expanded CD8+ TEMRA cells in cerebrospinal fluid (CSF) of three AD patients. Deep TCR sequencing, machine learning, and peptide screens identified the HLA-B*08:01-restricted Epstein-Barr virus trans-activator protein BZLF1 as the cognate antigen of a novel AD CSF TCR . These results provide the first evidence of clonal, antigen-specific T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration
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