title: Kidney transplantation: analysis of the expression and T cell-mediated activation of latent TGF-β.
abstract: Activated T cells infiltrate a renal allograft during rejection and can respond to TGF-β within the tubules, causing local differentiation and expression of the αE(CD103)β7 integrin. This study was performed to examine the expression of latent TGF-β within renal allograft tissues and to define a mechanism by which T cells can activate and respond to this latent factor. Rejecting renal allograft biopsy tissues showed increased expression of the latent TGF-β complex, which was localized around the tubules by a mechanism that might involve interaction with heparan sulfate in the basement membrane. A cultured renal TEC line also expressed the latent complex, but these cells did not respond to this form of TGF-β by pSmad 3. However, coculture of these cells with activated T cells induced the expression of CD103, suggesting that T cells can activate and respond to the latent TGF-β associated with TEC. Although activated T cells expressed little cell-surface TSP-1, this was increased by culture with fibronectin or fibronectin-expressing renal TEC. Blockade of TSP-1 using LSKL peptides reduced the potential of activated T cells to differentiate in response to latent TGF-β. This study suggests that penetration of renal tubules by activated T cells leads to increased expression of T cell-surface TSP-1, allowing activation of latent TGF-β sequestered on heparan sulfate within the microenvironment. This mechanism may be important for localized phenotypic maturation of T cells that have infiltrated the kidney during allograft rejection.
authors.affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Joseph D P
authors.initials: JD
authors.lastname: Willet
authors.forename: Watchara
authors.initials: W
authors.lastname: Pichitsiri
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Jenkinson
authors.forename: John G
authors.initials: JG
authors.lastname: Brain
authors.forename: Katrina
authors.initials: K
authors.lastname: Wood
authors.forename: Abd A
authors.initials: AA
authors.lastname: Alhasan
authors.forename: Julia
authors.initials: J
authors.lastname: Spielhofer
authors.forename: Helen
authors.initials: H
authors.lastname: Robertson
authors.forename: Simi
authors.initials: S
authors.lastname: Ali
authors.forename: John A
authors.initials: JA
authors.lastname: Kirby
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006497:Heparan Sulfate / Q000276:immunology / Q000378:metabolism; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D007684:Kidney Tubules / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D006497:Heparan Sulfate; D039001:Integrin alpha Chains; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C497790:SMAD3 protein, human; C481348:SPZ1 protein, human; C091367:alpha E integrins