title: Aire controls mesenchymal stem cell-mediated suppression in chronic colitis.
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.
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts, USA. biju_parekkadan@hms.harvard.edu
authors.forename: Biju
authors.initials: B
authors.lastname: Parekkadan
authors.forename: Anne L
authors.initials: AL
authors.lastname: Fletcher
authors.forename: Matthew
authors.initials: M
authors.lastname: Li
authors.forename: Melissa Y
authors.initials: MY
authors.lastname: Tjota
authors.forename: Angelique
authors.initials: A
authors.lastname: Bellemare-Pelletier
authors.forename: Jack M
authors.initials: JM
authors.lastname: Milwid
authors.forename: Je-Wook
authors.initials: JW
authors.lastname: Lee
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Turley
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000096927:AIRE Protein
chemical_list: D053495:Osteopontin; D014157:Transcription Factors; D000096927:AIRE Protein