Disruption of metabolic licensing by JAK inhibitors constrains CD8 T cell activation and effector function

Janus kinase inhibitors (JAKis) are widely prescribed for autoimmune diseases, but their use is associated with increased infection risk. The mechanisms underlying this susceptibility remain unclear. CD8 T cells play a central role in antimicrobial defense, yet little is known about how JAKis reprogram their activation and effector programs. Here, we investigated naïve 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. Functionally, JAKi-treated CD8 T cells exhibited reduced activation and produced lower amounts of cytokines and cytotoxic molecules. Notably, even JAKi-treated memory CD8 T cells that upregulated CD69 and CD25 failed to engage glycolysis, showing decreased GLUT1 expression and glucose uptake. 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 mTOR activity and increased p53-associated transcripts, consistent with impaired growth and stress signaling. CD8 T cells from rheumatoid arthritis patients under JAKi therapy were analyzed ex vivo for translational validation. These cells showed similar metabolic and signaling alterations, underscoring their clinical relevance. Altogether, these findings identify JAKis as disruptors of metabolic and signaling pathways in CD8 T cells, providing a mechanistic link between impaired effector function and the increased infection risk observed in treated patients.