MAdCAM-1 Co-stimulation Combined with Retinoic Acid and TGF-β Induces Blood CD8+ T cells to Adopt a Gut CD101+ TRM Phenotype

Abstract

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 MAdCAM-1, a ligand for the gut homing receptor α₄β₇ integrin, in the presence of retinoic acid and TGF-β provide a costimulatory signal that induces blood 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 CCR5, CCR9 and α₄β₇, three receptors associated with gut homing. A subset also express 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 T_RMs and provides a means to expand these cells in vitro, thereby affording an avenue to generate more effective tissue specific immunotherapies.

Keywords: CCR9; E-cadherin; MAdCAM-1; Tissue Resident Memory cells; α(4)β(7); α(E)β(7).