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

Transplantation. 2003 Feb 27;75(4):505-14. doi: 10.1097/01.TP.0000045708.39879.C7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / analysis
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • Cell Adhesion / immunology
  • Cell Division / immunology
  • Cell Line, Transformed
  • Chronic Disease
  • Graft Rejection / immunology*
  • Humans
  • In Vitro Techniques
  • Integrin alpha Chains / analysis
  • Interleukin-15 / immunology*
  • Kidney Transplantation / immunology*
  • Kidney Tubules / cytology
  • Kidney Tubules / immunology
  • Lymphocyte Culture Test, Mixed
  • Nephritis, Interstitial / immunology*
  • T-Lymphocytes / chemistry
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Transforming Growth Factor beta / immunology*
  • Transplantation, Homologous


  • Antigens, CD
  • Integrin alpha Chains
  • Interleukin-15
  • Transforming Growth Factor beta
  • alpha E integrins