Tubulitis and Epithelial Cell Alterations in Mouse Kidney Transplant Rejection Are Independent of CD103, Perforin or Granzymes A/B

One of the defining lesions of kidney allograft rejection is epithelial deterioration and invasion by inflammatory cells (tubulitis). We examined epithelial changes and their relationship to effector T cells and to CD103/E‐cadherin interactions in mouse kidney allografts. Rejecting allografts showed interstitial mononuclear infiltration from day 5. Loss of epithelial mass, estimated by tubular surface area, and tubulitis were minimal through day 7 and severe by day 21. Tubules in day 21 allografts manifested severe reduction of E‐cadherin and Ksp‐cadherin by immunostaining with redistribution to the apical membrane, indicating loss of polarity. By flow cytometry T cells isolated from allografts were 25% CD103+. Laser capture microdissection and RT‐PCR showed increased CD103 mRNA in the interstitium and tubules. However, allografts in hosts lacking CD103 developed tubulitis, cadherin loss, and epithelial deterioration similar to wild‐type hosts. The loss of cadherins and epithelial mass was also independent of perforin and granzymes A and B. Thus rejection is characterized by severe tubular deterioration associated with CD103+ T cells but not mediated by CD103/cadherin interactions or granzyme‐perforin cytotoxic mechanisms. We suggest that alloimmune effector T cells mediate epithelial injury by contact‐independent mechanisms related to delayed type hypersensitivity, followed by invasion of the altered epithelium to produce tubulitis. The hallmark of kidney rejection, tubulitis, is associated with profound changes in the epithelium (e.g. loss of cadherins), and does not require the cytotoxic functions of lymphocytes, suggesting that tubulitis is an indirect consequence of the inflammatory process in the interstitium rather than a lymphocyte attack on the epithelium.