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

Resident memory T cells (Ts) 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 αβ 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-like phenotype. These cells express CD103 (integrin α) and CD69, the two major T cell-surface markers, along with CD101. They also express C-C motif chemokine receptors 5 (CCR5) , C-C motif chemokine receptors 9 (CCR9), and αβ, three receptors associated with gut homing. A subset also expresses E-cadherin, a ligand for αβ. Fluorescent lifetime imaging indicated an αβ 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.