Tubulitis in renal allograft transforming growth rejection:: Role of transforming factor-β and interleukin-15 in development and maintenance of CD103+ intraepithelial T cells

Background. Renal tubules normally show no lymphocyte infiltration, but tubulitis is a feature of renal allograft rejection with many intratubular T cells expressing CD8 and CD103 (the alphaEbeta7 integrin). We investigated the development and maintenance of allospecific CD103(+) T cells within the tubular microenvironment. Methods. Mixed lymphocyte cultures were supplemented with transforming growth factor (TGF)-beta1 to model the expression and function of CD103 observed in situ on intratubular lymphocytes. Immunocytochemical techniques were used to identify cells coexpressing CD8 and interleukin (IL)-15Ralpha, to enumerate proliferating intratubular T cells, and to quantify IL-15 expression within the tubules of control and rejection-graded transplant biopsy specimens. These results were compared with a parallel analysis of the phenotype and proliferation of allospecific T cells expanded in vitro in the presence of TGF-beta1 and IL-15. Results. TGF-beta1 only induced the expression of adhesive CD103 after at least one cycle of alloantigen-specific cell division in vitro. In the renal allograft, a similar proportion of intratubular T cells was observed to proliferate during and after acute rejection. Tubular epithelial cells expressed IEL-15 constitutively, whereas intratubular CD8(+) T cells expressed IL-15 receptor a. IL-15 and TGF-beta1 synergized to promote expansion and survival of allospecific CD8(+)CD103(+) T cells in vitro, but 11,15 down-regulated perforin expression. Conclusions. These results suggest that activated, allospecific CD8(+) T cells are recruited to tubules during acute rejection where they encounter TGF-beta, up-regulate CD103 expression, and bind E-cadherin. A proportion of these cells proliferates and is maintained in a state of low perforin expression by the combined action of TGF-beta and. IL-15.