title: Differential expression of Smad7 transcripts identifies the CD4+CD45RChigh regulatory T cells that mediate type V collagen-induced tolerance to lung allografts.
abstract: Regulatory T cells (Tregs) induced by oral tolerance may suppress immunity by production of TGF-beta that could also enhance Treg activity. However, all cells that are phenotypically Tregs in rats (CD4(+)CD45RC(high)-RC(high)) may not have regulatory function. Because Smad7 expression in T cells is associated with inflammation and autoimmunity, then lack of Smad7 may identify those cells that function as Tregs. We reported that feeding type V collagen (col(V)) to WKY rats (RT1(l)) induces oral tolerance to lung allografts (F344-RT1(lvl)) by T cells that produce TGF-beta. The purpose of the current study was to identify the Tregs that mediate col(V)-induced tolerance, and determine Smad7 expression in these cells. RC(high) cells from tolerant rats were unresponsive to allogeneic stimulation and abrogated rejection after adoptive transfer. In contrast, CD4(+)CD45RC(low) (RC(low)) cells from tolerant rats and RC(high) or RC(low) cells from normal rats or untreated allograft recipients proliferated vigorously in response to donor Ags, and did not suppress rejection after adoptive transfer. TGF-beta enhanced proliferation in response to col(V) presented to tolerant RC(high), but not other cells. In contrast to other cells, only RC(high) cells from tolerant rats did not express Smad7. Collectively, these data show that the Tregs that mediate col(V)-induced tolerance to lung allografts do not express SMAD7 and, therefore, are permissive to TGF-beta-mediated signaling.
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Mizobuchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yasufuku
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.forename: M Azizul
authors.initials: MA
authors.lastname: Haque
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Heidler
authors.forename: Kena
authors.initials: K
authors.lastname: Woods
authors.forename: Gerald N
authors.initials: GN
authors.lastname: Smith
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Cummings
authors.forename: Takehiko
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Janice S
authors.initials: JS
authors.lastname: Blum
authors.forename: David S
authors.initials: DS
authors.lastname: Wilkes
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002478:Cells, Cultured; D018920:Coculture Techniques; D024062:Collagen Type V / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D017493:Leukocyte Common Antigens / Q000096:biosynthesis*; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051906:Smad7 Protein; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology; D023001:Transplantation Tolerance / Q000235:genetics
chemical_list: D024062:Collagen Type V; D004268:DNA-Binding Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D017493:Leukocyte Common Antigens