An Immunosenescent CD8+ T Cell Subset in Patients with Axial Spondyloarthritis and Psoriatic Arthritis Links Spontaneous Motility to Telomere Shortening and Dysfunction

Abstract

Objective

A pathogenetic role of CD8+ T lymphocytes in radiographic axial spondyloarthritis (r-axSpA) and other spondyloarthritis (SpA) is sustained by genome-wide association studies and by the expansion of public T cell clonotypes in the target tissues. This study investigates the migration of CD8+ T cells along with their phenotype and functions in patients with r-axSpA and psoriatic arthritis (PsA).

Methods

Peripheral blood CD8+ and CD4+ T cells were isolated from patients with r-axSpA (n = 128), PsA (n = 60), and rheumatoid arthritis (RA) (n = 74) and healthy donors (HDs) (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 sequencing analysis, whereas telomere length and dysfunction were measured by reverse transcriptase–polymerase chain reaction and immunofluorescence-fluorescence in situ hybridization, respectively.

Results

A significantly higher number of CD8+ T cells migrating in the absence of chemokine stimuli was found in patients with SpA compared with HDs and patients with RA. This subset, producing cytotoxic (granzyme B, perforin, granulysin) and proinflammatory molecules (tumor necrosis factor), was significantly enriched in terminally differentiated (CCR7−CD45RA+) and senescent (CD28−CD57+) cells having a gene expression profile characterized by cytolytic signature and natural killer markers. Remarkably, these spontaneously migrating CD8+ T cells showed DNA damage response activation, telomere shortening, and dysfunction.

Conclusion

These data describe a terminally differentiated CD8+ T cell subset with a senescent and cytotoxic/proinflammatory profile and an intrinsic invasive potential enriched in patients with SpA that represents a possible player in disease pathogenesis.