Tubulitis after renal transplantation:: Demonstration of an association between CD103+T cells, transforming growth factor β1 expression and rejection grade

Background Tubulitis is a defining feature for the diagnosis and management of acute renal allograft rejection, Lymphocytes extracted from rejecting renal tissue are known to express the alpha (E)beta (7)-integrin (CD103), a receptor for E-cadherin expressed on epithelial cells, In this study, expression of CD103 was examined in situ in tubulitis associated with acute rejection. Methods. Immuno-labeling detected CD8+ and CD103+ lymphocytes and E-cadherin on epithelial cells in cryostat sections from 34 diagnostic biopsy specimens and a limited number of transplant nephrectomies. CD8+ and CD103+ intratubular cells were enumerated as mean numbers per tubular cross-section and median values were compared between rejection grades as were median ratios of CD103+ to CD8+ cells. Active transforming growth factor (TGF) beta (1) was quantified in paraffin sections by immunofluorescence and confocal microscopical analysis. A parallel in vitro study quantified CD103+ T cells after allospecific activation with and without exogenous TGF beta (1). Results. CD8+ T cells were present in tubules and tubular interstitium in acute rejection. CD103+ T cells were restricted exclusively to the tubules. The numbers of intratubular CD8+ and CD103+ cells and the ratio of intratubular CD103+ to CD8+ cells increased significantly with tubulitis score (P values 0.005, 0.009, and 0.02, respectively). TGF beta (1) expression was wide-spread in tubules also increasing significantly with tubulitis score (P=0.034), In chronic rejection, CD103+ T cells and TGF beta (1) were present within both tubules and interstitial cell populations. The in vitro study demonstrated that addition of TGF beta (1) to activated, alloantigen-specific T cells increased the proportion of CD8+ cells that also expressed CD103. Conclusions. These data indicate that specific upregulation of the alpha (E)beta (7)-integrin by activated, intratubular T cells in acute renal allograft rejection could be a consequence of exposure to high local concentrations of TGF beta (1). The capacity of CD103+ T cells to bind E-cadherin on tubular epithelial cells may be an important factor in the pathogenesis of specific tissue damage observed in acute renal allograft rejection.