Gregg Allen Hadley

Regulation of CD103 Expression by CD8 + T Cells Responding to Renal Allografts

CD103 is an integrin with specificity for the epithelial cell-specific ligand, E-cadherin. Recent studies indicate that CD103 expression endows peripheral CD8 cells with a unique capacity to access the epithelial compartments of organ allografts. In the present study we used a nonvascularized mouse renal allograft model to 1) define the mechanisms regulating CD103 expression by graft-infiltrating CD8 effector populations, and 2) identify the cellular compartments in which this occurs. We report that CD8 cells responding to donor alloantigens in host lymphoid compartments do not initially express CD103, but dramatically up-regulate CD103 expression to high levels subsequent to migration to the graft site. CD103+CD8+ cells that infiltrated renal allografts exhibited a classic effector phenotype and were selectively localized to the graft site. CD8 cells expressing low levels of CD103 were also present in lymphoid compartments, but three-color analyses revealed that these are almost exclusively of naive phenotype. Adoptive transfer studies using TCR-transgenic CD8 cells demonstrated that donor-specific CD8 cells rapidly and uniformly up-regulate CD103 expression following entry into the graft site. Donor-specific CD8 cells expressing a dominant negative TGF-β receptor were highly deficient in CD103 expression following migration to the graft, thereby implicating TGF-β activity as a dominant controlling factor. The relevance of these data to conventional (vascularized) renal transplantation is confirmed. These data support a model in which TGF-β activity present locally at the graft site plays a critical role in regulating CD103 expression, and hence the epitheliotropism, of CD8 effector populations that infiltrate renal allografts.

Integrin‐mediated interactions influence the tissue specificity of CD8+ cytolytic T lymphocytes

We previously reported that CD8+ cytotoxic T lymphocytes (CTL) elicited in response to allogeneic renal epithelial cells (anti‐REC CTL) preferentially lyse REC targets as compared to conventional lymphoid cell (LC) targets. It is often tacitly assumed that such cell type specificity results from CTL recognition of tissue‐restricted MHC / peptide complexes. However, we herein report that anti‐REC CTL uniquely express CD103, an integrin with known specificity for the epithelial cell‐restricted ligand E‐cadherin, and are deficient in expression of CD11a (LFA‐1), an integrin known to play a critical accessory role in promoting lysis of LC targets. We demonstrate that CD8+ CTL clones with disparate CD103 / CD11a phenotypes but identical specificities for allo‐MHC / peptide can exhibit marked differences in cell type specificity. Antibody blocking studies provided direct evidence that CD103 serves as an accessory molecule that promotes lysis of REC targets. Taken together, these data indicate that integrin‐mediated accessory interactions can influence the capacity of CD8+ CTL to discriminate between different cell types.

T Cell-Epithelial Cell Interactions in Organ Allograft Rejection

The destruction of graft epithelial compartments by host T effector populations has long been recognized as a critical component of organ allograft rejection. For example, influx of host T cells into the graft renal tubular epithelium (tubulitis) is a prime diagnostic indicator of clinical renal allograft rejection’2. The afferent pathways leading to the generation of donor-specific T-effector populations and their initial recruitment into the graft have been the focus of extensive research in recent years and, consequently, have been elucidated in exquisite detail. In contrast, the efferent pathways in which armed T-effector populations gain access to, and subsequently destroy, graft epithelial compartments have received relatively little attention. This is an important omission because epithelial layers comprise the functional elements of most organ allografts. Thus, destruction of the graft epithelium by T-effector populations is a defining feature of the rejection process. An improved understanding of T-effector—epithelial interactions is likely to provide novel targets for therapeutic intervention in acute and chronic rejection of organ allografts. This chapter will review recent advances in our understanding of interactions between T-effector populations and the graft epithelium with emphasis on renal allograft rejection as a model of solid organ transplantation.