Disruption of metabolic licensing by JAK inhibitors constrains CD8+ T cell activation and effector function.
The Janus kinase inhibitors (JAKis) are widely prescribed in autoimmune diseases, but their use is associated with increased infection risk. The mechanisms underlying this susceptibility remain unclear. CD8 T cells are central for antimicrobial defense, yet little is known about how JAKis reprogram their activation and effector programs. Here we investigated naive and memory CD8 T cells from healthy donors stimulated in vitro with baricitinib, tofacitinib, or upadacitinib. Flow cytometry, SCENITH, transmission electron microscopy, and RNA-seq were used to evaluate metabolic and functional programs. We found that JAKis uncoupled phenotypic activation from metabolic reprogramming. Treated cells that expressed CD69 and CD25 failed to engage glycolysis, showing reduced GLUT1 expression and lower glucose uptake. Functionally, JAKi-treated CD8 T cells displayed reduced cytokine production and cytotoxic molecule expression. SCENITH profiling confirmed diminished glucose dependence and a shift toward mitochondrial reliance, despite reduced mitochondrial potential and structural alterations. Transcriptomic and protein analyses further revealed decreased p-mTOR and increased p53, consistent with impaired growth and stress signaling. Ex vivo CD8 T cells from rheumatoid arthritis patients under JAKi therapy were analyzed for translational validation. Similar alterations were observed in patient-derived T cells, underscoring clinical relevance. These findings identify JAKis as disruptors of metabolic and signaling pathways in CD8 T cells, linking impaired effector capacity with the infection risk observed in patients.