Tofacitinib treatment of Rheumatoid Arthritis: increases senescent T cell frequency in patients and limits T cell function in vitro

ALAMINO, VANINA A; ONOFRIO, LUISINA I; DEL VALLE ACOSTA, CRISTINA; FERRERO, PAOLA V; ZACCA, ESTEFANÍA R; CADILE, ISAAC I; MUSSANO, EDUARDO D; ONETTI, LAURA B; MONTES, CAROLINA L; GRUPPI, ADRIANA; ACOSTA RODRIGUEZ, EVA V

EUROPEAN JOURNAL OF IMMUNOLOGY

WILEY-V C H VERLAG GMBH

Año: 2023

0014-2980

Unravelling the immune signatures in rheumatoid arthritis (RA) patients receiving various treatment regimens can aid in comprehending the immune mechanisms´ role in treatment efficacy and side effects. Given the critical role of cellular immunity in RA pathogenesis, we sought to identify T cell profiles characterizing RA patients under specific treatments.We compared 75 immunophenotypic and biochemical variables in healthy donors (HD) and RA patients, including those receiving different treatments as well as treatment-free patients. Additionally, we conducted in vitro experiments to evaluate the direct effect of tofacitinib on purified naïve and memory CD4+ and CD8+ T cells.Multivariate analysis revealed that tofacitinib-treated patients segregated from HD at the expense of T-cell activation, differentiation and effector function related variables. Additionally, tofacitinib led to an accumulation of peripheral senescent memory CD4+ and CD8+ T cells. In vitro, tofacitinib impaired the activation, proliferation, and effector molecule expression and triggered senescence pathways in T cell subsets upon TCR-engagement, with the most significant impact on memory CD8+ T cells.Our findings suggest that tofacitinib may activate immunosenescence pathways while simultaneously inhibiting effector functions in T cells, both effects likely contributing to the high clinical success and reported side effects of this JAK inhibitor in RA.