MAdCAM-1 Co-Stimulation Combined with Retinoic Acid and TGF-(3 Induces Blood CD8+T Cells to Adopt a Gut CD101+TRM Phenotype

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 mucosal vascular addressin cell adhesion molecule 1, a ligand for the gut-homing receptor a4(37 integrin, in the presence of retinoic acid and transforming growth factor-(3 (TGF-(3) provides a co-stimulatory signal that induces blood cluster of differentiation (CD8+ T cells to adopt a TRM-like phenotype. These cells express CD103 (integrin aE) and CD69, the two major TRM cell-surface markers, along with CD101. They also express C-C motif chemokine receptors 5 (CCR5) , C-C motif chemokine receptors 9 (CCR9), and a4(37, three receptors associated with gut homing. A subset also expresses E-cadherin, a ligand for aE(37. Fluorescent lifetime imaging indicated an aE(37 and Ecadherin 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.