CD103+CTL accumulate within the graft epithelium during clinical renal allograft rejection

Background. We have previously reported that activated CD8+TCR alpha betacells that express high levels of the beta7 integrin CD103 (formerly alpha (E), MLA) are present at the graft site during clinical renal allograft rej ection. This observation potentially provides new insight into the mechanis ms underlying renal allograft destruction because the ligand of CD103 is th e epithelial cell-specific molecule E-cadherin, which is known to be expres sed by critical graft functional elements such as the renal tubular epithel ium. We herein used combined fluorescence-activated cell sorter (FACS) and immunohistochemical (IHC) analyses of transplant nephrectomy (TN) specimens to demonstrate that CD103+ cytolytic T lymphocytes (CTLs) specifically hom e to the graft epithelium during rejection episodes. Methods. Serial sections of TN specimens undergoing histologically confirme d cellular rejection (n=7) were stained with anti-CD8 or anti-CD103 and wer e scored for the presence of positively stained cells within the tubular ba sement membrane. Freshly isolated graft-infiltrating lymphocytes were subje cted to three-color FACS analyses to define the extended phenotypic charact eristics of CD103+ cells detected by IHC. Results. CD103+ cells in all specimens were biased towards an intratubular localization. On average, the percentage of CD103+ cells with an intraepith elial localization was 52.2 +/- 13.1 compared to 12.0 +/-3.5 for pan CD8+ c ells (mean +/- SE, n=5). FACS analyses confirmed that CD103+ cells detected by IHC exhibited the salient characteristics of CD8+ CTLs (large CD8+TCR a lpha beta+ CD62L(-)CD11a(hi)perforin+). The CD103- subset of graft-infiltra ting CD8 cells also exhibited a CTL phenotype, but these were predominantly restricted to the graft interstitium. Conclusions. These data implicate CD103 as a homing receptor that targets g raft-infiltrating CD8+ CTLs to the graft epithelium. Given the strong assoc iation of tubulitis with clinical rejection, these data are consistent with a role for the CD103+ CTL subset as an effector mechanism in renal allogra ft destruction.