The JAK inhibitor tofacitinib activates immunosenescence pathways and limits activation and function of t lymphocytes

ONOFRIO LUISINA; ALAMINO VANINA; FERRERO PAOLA; ACOSTA CRISTINA; WERNER MARINA; LAURA ONETTI; CADILE IGNACIO; EDUARDO MUSSANO; MONTES CAROLINA; ADRIANA GRUPPI; ACOSTA RODRÍGUEZ EVA

Congreso; Reunión Annual de Sociedades de Biociencias SAIC, SAI&FAIC, SAFIS.; 2023

SAIC, SAI&FAIC, SAFIS.

Tofacitinib (Tofa) is a Jak1/3 inhibitor that blocks the intracellular signaling of inflammatory cytokines and is used for treatment in Rheumatoid Arthritis (RA). Tofa is very effective to achieve disease remission but it is associated to higher herpes zoster incidence and tuberculosis reactivation likely due to immune alterations. While several studies have evaluated the effects of Tofa on the immune system, knowledge about its impact on activation and differentiation of T lymphocytes (TL) is scarce. Our previous results showed that TL from Tofa-treated RA patients exhibit a phenotype of terminal differentiation and immunosenescence. In this context, we aimed at assessing the impact of Tofa in vitro on TL activation and function focusing on possible differences according to naive vs. memory TL differentiation status. To this end, we activated TL sorted from healthy donors PBMCs with a-CD3/a-CD28 for 3 days in presence or absence of Tofa (1 to 10 uM). Tofa significantly reduced TL activation as evidenced by a decrease in the frequency of CD25+, T-bet+ and Ki-67+ cells. These effects were dose-dependent and observed in all the subsets but stronger in memory, particularly CD8+ TL. Reduced TL activation was associated with the upregulation of KLRG1, a pre-senescence marker, only in CD8 memory cells. In addition, Tofa reduced the effector function of all TL subpopulations evaluated as highlighted by the decreased frequency of cells expressing IL-2, IFNy and granzyme B. Interestingly, Tofa increased the expression of markers associated to cellular senescence like p-ATM and γH2AX, two kinases involved in the earliest stage of cellular response to DNA Double-Strand Break formation. The maximal effect size was detected in CD8 memory TL. Altogether, our findings suggest that Tofa trigger immunosenescence pathways in TL that could underlie its biological effects in RA but also be involved in its side effects by restraining the activity of memory TL involved in microbial control.