Background/Purpose: Ankylosing Spondylitis (AS) is characterized by chronic inflammation which underlies the pain and precedes spinal ankylosis. The strongest genetic association with AS is the HLA-B27, implicating involvement of CD8+ cytotoxic T cells (CTL) in AS pathogenesis. To date, the CTL compartment that underlies AS inflammation has yet to be fully defined. Our lab recently reported altered cytotoxicity profiles in CTL from AS patients, suggesting that dysregulated CTL with a cytotoxic phenotype are recruited to the joints. These findings suggest a central role of dysregulated CTLs in AS pathogenesis, warranting further investigation. Here we sought to characterize CTL subsets and immune checkpoint (IC) expression on CTL from patients with AS.

Methods: We performed immunophenotyping of peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) by flow cytometry. A 21- marker mass cytometry time-of-flight (CyTOF) panel is currently being developed to comprehensively assess the CTL compartment in AS patients.

Results: We identified a sub-cohort of AS patients with an enriched population of terminally differentiated memory CTL (up to 46.2% of all CD8⁺ T cells, expressing CD45RA⁺CCR7^–) in the periphery and elevated expression of the IC molecules PD-1 (18.3% vs 10.2% of total CD8⁺ T cells) & TIGIT (17.3% vs. 4.4% of total CD8⁺ T cells) on AS CTL compared to healthy controls. Effector memory CTL (CD45RA^–CCR7^–) were highly enriched in the SF. PD-1 expression is also highly upregulated in the synovial CTL (up to 75% of CD8⁺ T cells), suggesting local immune activation. Despite PD-1 upregulation in these CTL subsets, evidence of immune exhaustion, as assessed by EOMES expression, was not found.

Conclusion: We demonstrate that CTL from AS patients are highly activated, and are characterized by a distinct immune phenotype which implicates an intrinsic CTL dysregulation in AS pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd8-t-cell-subsets-and-immune-checkpoint-profiles-in-ankylosing-spondylitis-implicate-dysregulation-of-cytotoxic-t-lymphocytes-ctl/