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

T cells activate latent TGF‐β by an LSKL peptide‐sensitive mechanism, suggesting a role for thrombospondin‐1 in T cell differentiation after kidney transplantation. 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.