Aire controls mesenchymal stem cell-mediated suppression in chronic colitis

Biju Parekkadan, Anne L Fletcher, Matthew Li, Melissa Y Tjota, Angelique Bellemare-Pelletier, Jack M Milwid, Je-Wook Lee, Martin L Yarmush, Shannon J Turley

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20 Citations (Scopus)

Abstract

Mesenchymal stem cells (MSCs) are emerging as a promising immunotherapeutic, based largely on their overt suppression of T lymphocytes under inflammatory and autoimmune conditions. While paracrine cross-talk between MSCs and T cells has been well-studied, an intrinsic transcriptional switch that programs MSCs for immunomodulation has remained undefined. Here we show that bone marrow-derived MSCs require the transcriptional regulator Aire to suppress T cell-mediated pathogenesis in a mouse model of chronic colitis. Surprisingly, Aire did not control MSC suppression of T cell proliferation in vitro. Instead, Aire reduced T cell mitochondrial reductase by negatively regulating a proinflammatory cytokine, early T cell activation factor (Eta)-1. Neutralization of Eta-1 enabled Aire(-/-) MSCs to ameliorate colitis, reducing the number of infiltrating effector T cells in the colon, and normalizing T cell reductase levels. We propose that Aire represents an early molecular switch imposing a suppressive MSC phenotype via regulation of Eta-1. Monitoring Aire expression in MSCs may thus be a critical parameter for clinical use.
Original languageEnglish
Pages (from-to)178 - 186
Number of pages9
JournalMolecular Therapy
Volume20
Issue number1
DOIs
Publication statusPublished - 2012
Externally publishedYes

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