Mucosal associated invariant T (MAIT) cells are antiâmicrobial innateâlike T cells that are abundant in blood and liver. MAIT cells express a semiâinvariant Tâcell receptor (TCR) that recognizes a pyrimidine ligand, derived from microbial riboflavin synthesis, bound to MR1. Both blood and liver derived (ld)âMAIT cells can be robustly stimulated via TCR or by cytokines produced during bacterial or viral infection. In this study, we compared the functional and transcriptomic response of human blood and ldâMAIT cells to TCR signals (Escherichia coli or the pyrimidine ligand) and cytokines (ILâ12 + ILâ18). While the response of blood and ldâMAIT cells to TCR signals were comparable, following cytokine stimulation ldâMAIT cells were more polyfunctional than blood MAIT cells. Transcriptomic analysis demonstrated different effector programmes of ldâMAIT cells with the two modes of activation, including the enrichment of a tissue repair signature in TCRâstimulated MAIT cells. Interestingly, we observed enhancement of ILâ12 signaling and fatty acid metabolism in untreated ldâMAIT cells compared with blood MAIT cells. Additionally, MAIT cells from blood and liver were modulated similarly by TCR and cytokine signals. Therefore, we report that blood and ldâMAIT cells are fundamentally different but undergo conserved changes following activation via TCR or by cytokines.