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Single Cell Immune Profiling in Ankylosing Spondylitis Reveals Resistance of CD8+ T cells to Immune Exhaustion

ABSTRACT: Persistent chronic inflammation is a hallmark of Ankylosing Spondylitis (AS), with cytotoxic T cells (CTLs) increasingly implicated in its pathogenesis. Ordinarily, T cell exhaustion follows sustained, persistent T cell activation to limit collateral tissue damage. Using mass cytometry and single-cell RNA sequencing (scRNA-seq), we identified a clonally expanded CTL subset in AS synovial fluid that expresses inhibitory receptors (PD-1, TIGIT, LAG-3) yet retains its effector capacity to express granzymes, perforin, TNF-a, and IFN-g. Gene expression profile of this CTL subset show downregulation of canonical exhaustion markers. 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 suggest these cells may differentiate into other effector CTL subsets. Our findings reveal a checkpoint-expressing CTL population in AS that resists exhaustion and retains an activated, effector phenotype. We propose that failure to undergo exhaustion may be a fundamental mechanism sustaining AS chronic inflammation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288581 | GEO | 2025/02/06

REPOSITORIES: GEO

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