MAdCAM-1 co-stimulation combined with retinoic acid and TGF-β induces blood CD8 + T cells to adopt a gut CD101 + T RM phenotype.

Resident memory T cells (T RM s) 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 mucosal vascular addressin cell adhesion molecule 1, a ligand for the gut-homing receptor α 4 β 7 integrin, in the presence of retinoic acid and transforming growth factor-β (TGF-β) provides a co-stimulatory signal that induces blood cluster of differentiation (CD8 + T cells to adopt a T RM -like phenotype. These cells express CD103 (integrin α E ) and CD69, the two major T RM cell-surface markers, along with CD101. They also express C-C motif chemokine receptors 5 (CCR5) , C-C motif chemokine receptors 9 (CCR9), and α 4 β 7 , three receptors associated with gut homing. A subset also expresses E-cadherin, a ligand for α E β 7 . Fluorescent lifetime imaging indicated an α E β 7 and 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 resident memory T cells and provides a means to expand these cells in vitro, thereby affording an avenue to generate more effective tissue-specific immunotherapies.