A novel immunosenescent CD8+ T cell subset in patients with Ankylosing Spondylitis and Psoriatic Arthritis links spontaneous motility to telomere shortening and dysfunction

Objectives: A pathogenetic role of CD8+ T lymphocytes in ankylosing spondylitis (AS) and other spondyloarthritis (SpA) is sustained by genome-wide association studies (GWAS) as well as the expansion of public T cell clonotypes in the target tissues. This study focuses on CD8+ T cells from AS and psoriatic arthritis (PsA) patients with the aim to correlate their phenotype and function with motility. Methods: Peripheral blood CD8+ and CD4+ T cells were isolated from AS (n= 128), PsA (n= 60) and rheumatoid arthritis (RA, n= 74) patients and healthy donors (HD, n= 79). Transwell migration assay was performed in the presence of different chemokines. CD8+ T cell immunoprofiling and effector functions were assessed by multiparametric flow cytometry. Transcriptome signature was evaluated by RNA-seq analysis while telomere length and dysfunction were measured by RT-PCR and IF-fluorescence in situ hybridization (FISH), respectively. Results: A significantly higher number of CD8+ T cells migrating in the absence of chemokine stimuli was found in patients with SpA compared to HD and RA patients. This subset, producing cytotoxic (granzyme B, perforin, granulysin) and inflammatory molecules (TNFα), was significantly enriched in terminally differentiated (CCR7-CD45RA+) and senescent (CD28-CD57+) cells with a gene expression profile characterized by cytolytic signature and natural killer (NK) markers. Of note, these spontaneously migrating CD8+ T cells showed activation of DNA damage response (DDR), telomere shortening and dysfunction. Conclusions: Our data describe a terminally differentiated CD8+ T cell subset with a senescent and cytotoxic/proinflammatory profile and an intrinsic invasive potential enriched in SpA patients that represents a possible player in disease pathogenesis.