THE JAK INHIBITOR TOFACITINIB ACTIVATES IMMUNOSENESCENCE PATHWAYS AND LIMITS ACTIVATION AND FUNCTION OF T LYMPHOCYTES.

Mar del Plata

Encuentro; Joint Meeting SAI, SAI & FAIC SAFI 2022; 2022

SAI, SAI, FAIC SAFI

Tofacitinib (Tofa) is a Jak1/3 inhibitor that blocks the intracellularsignaling of inflammatory cytokines and is used for treatment inRheumatoid Arthritis (RA). Tofa is very effective to achieve diseaseremission but it is associated to higher herpes zoster incidence andtuberculosis reactivation likely due to immune alterations. Whileseveral studies have evaluated the effects of Tofa on the immunesystem, knowledge about its impact on activation and differentiationof T lymphocytes (TL) is scarce. Our previous results showedthat TL from Tofa-treated RA patients exhibit a phenotype of terminaldifferentiation and immunosenescence. In this context, we aimedat assessing the impact of Tofa in vitro on TL activation and functionfocusing on possible differences according to naive vs. memoryTL differentiation status. To this end, we activated TL sorted fromhealthy donors PBMCs with a-CD3/a-CD28 for 3 days in presenceor absence of Tofa (1 to 10 uM). Tofa significantly reduced TL activationas evidenced by a decrease in the frequency of CD25+, T-bet+and Ki-67+ cells. These effects were dose-dependent and observedin all the subsets but stronger in memory, particularly CD8+ TL. ReducedTL 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 evaluatedas highlighted by the decreased frequency of cells expressing IL-2,IFNy and granzyme B. Interestingly, Tofa increased the expression ofmarkers associated to cellular senescence like p-ATM and γH2AX,two kinases involved in the earliest stage of cellular response toDNA Double-Strand Break formation. The maximal effect size wasdetected in CD8 memory TL. Altogether, our findings suggest thatTofa trigger immunosenescence pathways in TL that could underlieits biological effects in RA but also be involved in its side effects byrestraining the activity of memory TL involved in microbial control.