An immunosenescent CD8+ T cell subset in patients with axial Spondyloarthritis and Psoriatic Arthritis links spontaneous motility to telomere shortening and dysfunction

Giorgia Paldino; Valentina Tedeschi; Valentina Proganò; Erica Salvati; Valerio Licursi; Eleonora Vertecchi; Alexandru L Bivolaru; Emanuele Molteni; Rossana Scrivo; Mattia Congia; Alberto Cauli; Rosalba Caccavale; Marino Paroli; Martina Kunkl; Loretta Tuosto; Rosa Sorrentino; Maria Teresa Fiorillo

doi:10.1002/art.43109

An immunosenescent CD8+ T cell subset in patients with axial Spondyloarthritis and Psoriatic Arthritis links spontaneous motility to telomere shortening and dysfunction

Arthritis Rheumatol. 2025 Jan 21. doi: 10.1002/art.43109. Online ahead of print.

Authors

Giorgia Paldino^#¹, Valentina Tedeschi^#¹, Valentina Proganò¹, Erica Salvati², Valerio Licursi², Eleonora Vertecchi², Alexandru L Bivolaru¹, Emanuele Molteni³, Rossana Scrivo³, Mattia Congia⁴, Alberto Cauli⁴, Rosalba Caccavale⁵, Marino Paroli⁵, Martina Kunkl^{1

6}, Loretta Tuosto¹, Rosa Sorrentino¹, Maria Teresa Fiorillo¹

Affiliations

¹ Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy.
² Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, Italy.
³ Rheumatology Unit, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
⁴ Rheumatology Unit, Azienda Ospedaliero-Universitaria di Cagliari, Cagliari, Italy.
⁵ Clinical Immunology Unit, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, ICOT Hospital, Sapienza University of Rome c/o Polo Pontino, Latina, Italy.
⁶ Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, Italy.

^# Contributed equally.

PMID: 39835465
DOI: 10.1002/art.43109

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 (GWAS) 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 r-axSpA (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 whereas 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 proinflammatory molecules (TNFα), 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 (NK) markers. Remarkably, these spontaneously migrating CD8+ T cells showed DNA damage response (DDR) 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 SpA patients that represents a possible player in disease pathogenesis.