title: IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease.
abstract: Systemic sclerosis (SSc) is a potentially fatal autoimmune disorder with limited therapeutic options. Sclerodermatous graft versus host disease (sclGvHD), induced by transfer of B10.D2 splenocytes into BALB/cRag2-/-mice, models an inflammatory subset of SSc characterized by a prominent IL13-induced gene expression signature in the skin. Host mice deficient in IL4RA, a subunit of the type II IL4/IL13 receptor, are protected from sclGvHD. While IL4RA has a well-established role in Th2 differentiation and alternative macrophage activation, we report here a previously unappreciated function for IL4RA in lymphatic endothelial cells (LECs): regulation of activated T cell egress. Seven days after splenocyte transfer,Il4ra-/-hosts had increased numbers of activated graft CD4+T cells in skin draining lymph nodes (dLNs) but fewer T cells in efferent lymph, blood, and skin. Sphingosine-1 phosphate (S1P), master regulator of lymphocyte egress from LNs, was lower in dLNs ofIl4ra-/-hosts with a corresponding decrease of S1P kinase 1 (Sphk1) expression in LECs. Bypassing the efferent lymphatics via i.v. injection of CD4+T cells from dLNs ofIl4ra-/-sclGvHD mice restored clinical GvHD in secondaryIl4ra-/-recipients. These results identify a role for IL4RA and suggest that modulation of lymphocyte egress from LNs may be effective in SSc and GvHD.
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Urso
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Alvarez
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Viviana
authors.initials: V
authors.lastname: Cremasco
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Tsang
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Grauel
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Ragon Institute of Massachusetts General Hospital (MGH), MIT, and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joerg
authors.initials: J
authors.lastname: Ermann
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Antonios O
authors.initials: AO
authors.lastname: Aliprantis