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

Resident memory T cells (T_RMs) 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 α₄β₇ 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 α₄β₇, three receptors associated with gut homing. A subset also expresses E-cadherin, a ligand for α_Eβ₇. Fluorescent lifetime imaging indicated an α_Eβ₇ 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.