Resistance of exhaustion in PD-1+TIGIT+LAG3+ CD8+ T cells characterize chronic joint inflammation in ankylosing spondylitis

ABSTRACT: Persistent chronic inflammation is the clinical hallmark of ankylosing spondylitis (AS). There is increasing evidence that cytotoxic T cells (CTLs) play a central role in AS pathogenesis. Chronic activation of CTLs is ordinarily followed by T cell exhaustion, which serves as a host homeostatic mechanism to limit collateral tissue damage resulting from persisting CTL effector functions. Using mass cytometry and single cell RNA sequencing (scRNA-seq), we identified a clonally expanded CTL subset in the inflamed synovial microenvironment from AS patients that, despite an expression of immune checkpoints (PD-1, TIGIT & LAG-3), retain their capacity to express granzymes, perforin, TNF-a, and IFN-g. Concurrent gene expression analysis using scRNA-seq reveals that genes that are canonically expressed in bona fide exhausted CTLs are downregulated in AS CTLs. We also observe that at the protein level, TOX, a critical transcription factor regulating CTL exhaustion, is downregulated in PD-1+TIGIT+LAG-3+CTLs. In silico trajectory analyses indicate that these CTLs may differentiate into other subsets of activated, effector CTLs. Thus, we have discovered an immune checkpoint expressing CTL subset in AS that resists T cell exhaustion, and paradoxically retains an activated, effector phenotype. We propose that evasion of T cell exhaustion represents a mechanism which could be fundamental to perpetuating inflammation in AS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288581 | GEO | 2025/02/06

REPOSITORIES: GEO