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 IL-15 constitutively, whereas intratubular CD8 T cells expressed IL-15 receptor alpha. IL-15 and TGF-beta1 synergized to promote expansion and survival of allospecific CD8 CD103 T cells in vitro, but IL-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.
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 IL-15 constitutively, whereas intratubular CD8 T cells expressed IL-15 receptor alpha. IL-15 and TGF-beta1 synergized to promote expansion and survival of allospecific CD8CD103 T cells in vitro, but IL-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.
Authors: Joseph D P Willet; Watchara Pichitsiri; Sarah E Jenkinson; John G Brain; Katrina Wood; Abd A Alhasan; Julia Spielhofer; Helen Robertson; Simi Ali; John A Kirby Journal: J Leukoc Biol Date: 2012-11-27 Impact factor: 4.962