title: Semaphorin 7a+ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-β1-induced pulmonary fibrosis.
abstract: BACKGROUND
  Lymphocytes are increasingly associated with idiopathic pulmonary fibrosis (IPF). Semaphorin 7a (Sema 7a) participates in lymphocyte activation.
  
  
  OBJECTIVE
  To define the relationship between Sema 7a and lymphocytes in IPF.
  
  
  METHODS
  We characterized the significance of Sema 7a+ lymphocytes in humans with IPF and in a mouse model of lung fibrosis caused by lung-targeted, transgenic overexpression of TGF-β1. We determined the site of Sema 7a expression in human and murine lungs and circulation and used adoptive transfer approaches to define the relevance of lymphocytes coexpressing Sema7a and the markers CD19, CD4, or CD4+CD25+FoxP3+ in TGF-β1-induced murine lung fibrosis.
  
  
  RESULTS
  Subjects with IPF show expression of Sema 7a on lung CD4+ cells and circulating CD4+ or CD19+ cells. Sema 7a expression is increased on CD4+ cells and CD4+CD25+FoxP3+ regulatory T cells, but not CD19+ cells, in subjects with progressive IPF. Sema 7a is expressed on lymphocytes expressing CD4 but not CD19 in the lungs and spleen of TGF-β1-transgenic mice. Sema 7a expressing bone marrow-derived cells induce lung fibrosis and alter the production of T-cell mediators, including IFN-γ, IL-4, IL-17A, and IL-10. These effects require CD4 but not CD19. In comparison to Sema 7a-CD4+CD25+FoxP3+ cells, Sema7a+CD4+CD25+FoxP3+ cells exhibit reduced expression of regulatory genes such as IL-10, and adoptive transfer of these cells induces fibrosis and remodeling in the TGF-β1-exposed murine lung.
  
  
  CONCLUSIONS
  Sema 7a+CD4+CD25+FoxP3+ regulatory T cells are associated with disease progression in subjects with IPF and induce fibrosis in the TGF-β1-exposed murine lung.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Reilkoff
authors.forename: Hong
authors.initials: H
authors.lastname: Peng
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Murray
authors.forename: Xueyan
authors.initials: X
authors.lastname: Peng
authors.forename: Thomas
authors.initials: T
authors.lastname: Russell
authors.forename: Ruth
authors.initials: R
authors.lastname: Montgomery
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.forename: Albert
authors.initials: A
authors.lastname: Shaw
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Mridu
authors.initials: M
authors.lastname: Gulati
authors.forename: Aditi
authors.initials: A
authors.lastname: Mathur
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.forename: Erica L
authors.initials: EL
authors.lastname: Herzog
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D016753:Interleukin-10 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039961:Semaphorins / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C485571:Sema7a protein, mouse; D039961:Semaphorins; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10