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Kidney transplantation: analysis of the expression and T cell-mediated activation of latent TGF-β.

Willet JD, Pichitsiri W, Jenkinson SE, Brain JG, Wood K, Alhasan AA, Spielhofer J, Robertson H, Ali S, Kirby JA - J. Leukoc. Biol. (2012)

Bottom Line: 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.Blockade of TSP-1 using LSKL peptides reduced the potential of activated T cells to differentiate in response to latent TGF-β.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.

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.

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Immunohistochemical localization of LTBP-1 and heavily sulfated heparan sulfate in human kidney.Representative sections showing low-level, tubule-associated LTBP-1 expression (stained brown with a blue Mayer's hematoxylin nuclear counterstain) in sections from normal kidney (A) and transplanted kidney (B) with no apparent rejection; this was greatly increased in transplanted kidneys with chronic inflammation and IF/TA (C). Heavily sulfated HS expressing the HS3A8 epitope (red TRITC immunofluorescence with a blue DAPI nuclear counterstain) was restricted to the narrow tubular basement membrane in normal kidney (D) and nonrejecting renal allograft tissue (E); this expression was increased and included the expanded interstitium in sections showing features of T cell infiltration with IF/TA (F). Relative quantification of the HS3A8 epitope in normal and chronic rejection transplant biopsy sections (G), showing increased expression associated with T cell infiltration and IF/TA (P<0.0001); the bars show mean values ± sem.
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Figure 1: Immunohistochemical localization of LTBP-1 and heavily sulfated heparan sulfate in human kidney.Representative sections showing low-level, tubule-associated LTBP-1 expression (stained brown with a blue Mayer's hematoxylin nuclear counterstain) in sections from normal kidney (A) and transplanted kidney (B) with no apparent rejection; this was greatly increased in transplanted kidneys with chronic inflammation and IF/TA (C). Heavily sulfated HS expressing the HS3A8 epitope (red TRITC immunofluorescence with a blue DAPI nuclear counterstain) was restricted to the narrow tubular basement membrane in normal kidney (D) and nonrejecting renal allograft tissue (E); this expression was increased and included the expanded interstitium in sections showing features of T cell infiltration with IF/TA (F). Relative quantification of the HS3A8 epitope in normal and chronic rejection transplant biopsy sections (G), showing increased expression associated with T cell infiltration and IF/TA (P<0.0001); the bars show mean values ± sem.

Mentions: Normal human kidney (Fig. 1A) and renal allograft tissue showing normal histology (Fig. 1B) expressed low levels of LTBP-1. However, an increased level of LTBP-1 was observed around most tubules and within the interstitium of sections showing T cell infiltration and IF/TA (Fig. 1C). The basement membrane of the tubules in normal kidney (Fig. 1D) and renal allografts with no or borderline rejection (Fig. 1E) expressed a low level of N-, 6O-, and 2O-sulfated HS. This was increased greatly in the thickened tubular basement membrane of remnant tubules and the interstitium in tissue with features of cellular infiltration (Fig. 1F). Figure 1G shows quantified expression of the HS3A8 epitope in kidney sections and indicates a significant increase (P<0.0001) in the expression of heavily sulfated HS in transplant sections showing cellular infiltration.


Kidney transplantation: analysis of the expression and T cell-mediated activation of latent TGF-β.

Willet JD, Pichitsiri W, Jenkinson SE, Brain JG, Wood K, Alhasan AA, Spielhofer J, Robertson H, Ali S, Kirby JA - J. Leukoc. Biol. (2012)

Immunohistochemical localization of LTBP-1 and heavily sulfated heparan sulfate in human kidney.Representative sections showing low-level, tubule-associated LTBP-1 expression (stained brown with a blue Mayer's hematoxylin nuclear counterstain) in sections from normal kidney (A) and transplanted kidney (B) with no apparent rejection; this was greatly increased in transplanted kidneys with chronic inflammation and IF/TA (C). Heavily sulfated HS expressing the HS3A8 epitope (red TRITC immunofluorescence with a blue DAPI nuclear counterstain) was restricted to the narrow tubular basement membrane in normal kidney (D) and nonrejecting renal allograft tissue (E); this expression was increased and included the expanded interstitium in sections showing features of T cell infiltration with IF/TA (F). Relative quantification of the HS3A8 epitope in normal and chronic rejection transplant biopsy sections (G), showing increased expression associated with T cell infiltration and IF/TA (P<0.0001); the bars show mean values ± sem.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928105&req=5

Figure 1: Immunohistochemical localization of LTBP-1 and heavily sulfated heparan sulfate in human kidney.Representative sections showing low-level, tubule-associated LTBP-1 expression (stained brown with a blue Mayer's hematoxylin nuclear counterstain) in sections from normal kidney (A) and transplanted kidney (B) with no apparent rejection; this was greatly increased in transplanted kidneys with chronic inflammation and IF/TA (C). Heavily sulfated HS expressing the HS3A8 epitope (red TRITC immunofluorescence with a blue DAPI nuclear counterstain) was restricted to the narrow tubular basement membrane in normal kidney (D) and nonrejecting renal allograft tissue (E); this expression was increased and included the expanded interstitium in sections showing features of T cell infiltration with IF/TA (F). Relative quantification of the HS3A8 epitope in normal and chronic rejection transplant biopsy sections (G), showing increased expression associated with T cell infiltration and IF/TA (P<0.0001); the bars show mean values ± sem.
Mentions: Normal human kidney (Fig. 1A) and renal allograft tissue showing normal histology (Fig. 1B) expressed low levels of LTBP-1. However, an increased level of LTBP-1 was observed around most tubules and within the interstitium of sections showing T cell infiltration and IF/TA (Fig. 1C). The basement membrane of the tubules in normal kidney (Fig. 1D) and renal allografts with no or borderline rejection (Fig. 1E) expressed a low level of N-, 6O-, and 2O-sulfated HS. This was increased greatly in the thickened tubular basement membrane of remnant tubules and the interstitium in tissue with features of cellular infiltration (Fig. 1F). Figure 1G shows quantified expression of the HS3A8 epitope in kidney sections and indicates a significant increase (P<0.0001) in the expression of heavily sulfated HS in transplant sections showing cellular infiltration.

Bottom Line: 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.Blockade of TSP-1 using LSKL peptides reduced the potential of activated T cells to differentiate in response to latent TGF-β.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.

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.

Show MeSH
Related in: MedlinePlus