Abstract Effector CD4+ T (Teff) lymphocytes infiltrate sites of inflammation and orchestrate the immune response by instructing local leukocytes. Mast cells (MCs) are tissue sentinel cells strategically located near blood vessels and T cell–rich areas. MC/Teff cell interactions shape Teff cell responses, but in turn, Teff cell action on MCs is still poorly understood. Here, we analyzed the human MC/Teff cell interplay through both the application of RNA sequencing and functional assays. We showed that activated Teff cells induce a specific transcriptomic program in MCs including production of both inflammatory cytokines and chemokines, prostaglandin, and a FcεRI-dependent degranulation facilitation, thereby driving them toward an inflammatory phenotype. Moreover, Teff cells induce in MCs the capacity to interact with CD4+ T cells through a wide range of dedicated soluble and membrane ligands and to play the role of antigen-presenting cells.