Regulation of the epithelial cell-specific integrin, CD103, by human CD8+ cytolytic T lymphocytes.

Abstract

The destruction of the graft epithelium by CD8+ cytolytic T lymphocytes (CTL) is an important aspect of organ allograft rejection. Our recent finding in a mouse model that the epithelial cell-specific integrin, CD103, defines a subset of CD8+ CTL potentially sheds new light onto such interactions. The goal of the present study was to assess the relevance of these data to the human system. CD103 expression by human T-cell populations generated in mixed lymphocyte cultures or isolated from transplant nephrectomy specimens was quantitated using multiparameter FACS analyses. CD103 defined a major subset (26-76%) of CD8+ CTL generated in human mixed lymphocyte cultures; cell sorting experiments confirmed that the CD103+ and CD103- subsets both possess allospecific lytic activity. Anti-transforming growth factor (TGF)-beta blocked the appearance of the CD103+ CTL subset, and persistent expression of CD103 by CD8+ CTL was dependent on bioactive TGF-beta. Isolated CD103+ and CD103- CD8 subsets maintained their phenotypic integrity during in vitro expansion, although optimal CD103 expression on the former was TGF-beta dependent. Although CD103+ cells were rare among activated CD8 cells in peripheral lymphoid compartments (< 10%), analyses of transplant nephrectomy specimens revealed that a major subset (21-61%) of CD8 memory/effector cells that infiltrate rejecting renal allografts express high levels of CD103. We conclude that CD103 defines a discrete and stable subset of human CD8+ CTL and that CD103 expression by such cells is initiated and maintained by bioactive TGF-beta. These data point to the existence of a human effector subset that is uniquely specialized for the destruction of the graft epithelium.