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Resident memory T cells (TRMs) help control local immune homeostasis and contribute to tissue protective immune responses. The local cues that guide their differentiation and localization are poorly defined. We demonstrate that MAdCAM-1, a ligand for the gut homing receptor α4β7integrin, in the presence of retinoic acid and TGF-β provide a costimulatory signal that induces blood CD8+T cells to adopt a TRM-like phenotype. These cells express CD103 (integrin αE) and CD69, the two major TRMcell surface markers, along with CD101. They also express CCR5, CCR9 and α4β7, three receptors associated with gut homing. A subset also express E-cadherin, a ligand for αEβ7. Fluorescent lifetime imaging indicated an αEβ7and E-cadherin cis interaction on the plasma membrane. This report advances our understanding of the signals that drive the differentiation of CD8+T cells into TRMs and provides a means to expand these cells in vitro, thereby affording an avenue to generate more effective tissue specific immunotherapies.