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

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. We sorted the CD38-CD127+PD-1int, CD38-CD127+PD-1-, CD38-CD127-PD-1intKLRG1+, PD-1hi and CD38hiCD127-PD-1int populations of CD8+ T cells from synovial fluid mononuclear cells of donors with checkpoint inhibitor-induced arthritis (CI), rheumatoid arthritis (RA), or psoriatic arthritis (PsA) to gene expression profiling using data obtained from RNA-seq. Please note that RNA-Seq raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns.