Single cell immune profiling in ankylosing spondylitis reveals resistance of CD8+ T cells to immune exhaustion
Summary: 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...
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Elsevier
2025-07-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225009769 |
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| author | Michael Tang Zoya Qaiyum Melissa Lim Robert D. Inman |
| author_facet | Michael Tang Zoya Qaiyum Melissa Lim Robert D. Inman |
| author_sort | Michael Tang |
| collection | DOAJ |
| description | Summary: 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-α, and IFN-γ. Gene expression profile of this CTL subset shows the 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 that 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. |
| format | Article |
| id | doaj-art-a8bf741fc8f94164a26ee84fa05a3e97 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-a8bf741fc8f94164a26ee84fa05a3e972025-08-20T02:42:37ZengElsevieriScience2589-00422025-07-0128711271510.1016/j.isci.2025.112715Single cell immune profiling in ankylosing spondylitis reveals resistance of CD8+ T cells to immune exhaustionMichael Tang0Zoya Qaiyum1Melissa Lim2Robert D. Inman3Spondylitis Program, Schroeder Arthritis Institute, University Health Network, Toronto, ON M5T0S8, CanadaSpondylitis Program, Schroeder Arthritis Institute, University Health Network, Toronto, ON M5T0S8, CanadaSpondylitis Program, Schroeder Arthritis Institute, University Health Network, Toronto, ON M5T0S8, CanadaSpondylitis Program, Schroeder Arthritis Institute, University Health Network, Toronto, ON M5T0S8, Canada; Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S1A8Canada; Division of Rheumatology, Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S3H2, Canada; Corresponding authorSummary: 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-α, and IFN-γ. Gene expression profile of this CTL subset shows the 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 that 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.http://www.sciencedirect.com/science/article/pii/S2589004225009769ImmunologyImmune responseTranscriptomics |
| spellingShingle | Michael Tang Zoya Qaiyum Melissa Lim Robert D. Inman Single cell immune profiling in ankylosing spondylitis reveals resistance of CD8+ T cells to immune exhaustion iScience Immunology Immune response Transcriptomics |
| title | Single cell immune profiling in ankylosing spondylitis reveals resistance of CD8+ T cells to immune exhaustion |
| title_full | Single cell immune profiling in ankylosing spondylitis reveals resistance of CD8+ T cells to immune exhaustion |
| title_fullStr | Single cell immune profiling in ankylosing spondylitis reveals resistance of CD8+ T cells to immune exhaustion |
| title_full_unstemmed | Single cell immune profiling in ankylosing spondylitis reveals resistance of CD8+ T cells to immune exhaustion |
| title_short | Single cell immune profiling in ankylosing spondylitis reveals resistance of CD8+ T cells to immune exhaustion |
| title_sort | single cell immune profiling in ankylosing spondylitis reveals resistance of cd8 t cells to immune exhaustion |
| topic | Immunology Immune response Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225009769 |
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