Post-transplant renal tubulitis: The recruitment, differentiation and persistence of intra-epithelial T cells

Tubulitis is used by the Banff protocol as a major criterion to grade acute renal allograft rejection. This review integrates results from in vitro and in vivo studies to develop a chronological model to explain the development and functions of tubular inflammation during the rejection process. Proteoglycan-immobilized chemokines are the primary motivators for the vectorial recruitment of specific immune cell populations from the blood, through the endothelium and interstitial tissues to the renal tubules. After penetration of the basement membrane, T cells encounter TGF-beta that can induce expression of the alphaEbeta7 integrin on proliferating cells. This allows adhesion to E-cadherin on the baso-lateral surfaces of tubular epithelial cells and provides an explanation for the epithelial-specific cytotoxicity observed during acute rejection. Tubular epithelium is also a rich source of IL-15 that can stimulate IL-15 receptor-expressing intratubular CD8+ T cells. This anti-apoptotic microenvironment may explain the long-term persistence of cycling T cells within intact tubules after episodes of acute rejection. These memory-like T cells may have local immunoregulatory properties, including the production of additional TGF-beta, but could also modify normal tubular homeostasis resulting in epithelial to mesenchymal transdifferentiation, tubulointerstitial fibrosis and, ultimately, graft failure.