Critical Role for CD103+CD8+ Effectors in Promoting Tubular Injury following Allogeneic Renal Transplantation

Abstract

Immune destruction of the graft renal tubules is an important barrier to the long-term function of clinical renal allografts, but the underlying mechanisms remain obscure. CD103—an integrin conferring specificity for the epithelial cell-restricted ligand, E-cadherin—defines a subset of CD8 effectors that infiltrate the graft tubular epithelium during clinical rejection episodes, predicting a causal role for CD103+CD8+ effectors in tubular injury. In the present study, we used rodent transplant models to directly test this hypothesis. Surprisingly, CD8 cells infiltrating renal allografts undergoing unmodified acute rejection did not express significant levels of CD103. However, we demonstrate that a brief course of cyclosporine A to rat renal allograft recipients promotes progressive accumulation of CD103+CD8+ cells within the graft, concomitant with the development of tubular atrophy and interstitial fibrosis. As in the known clinical scenario, graft-associated CD103+CD8+ cells exhibited a T effector phenotype and were intimately associated with the renal tubular epithelium. Treatment with anti-CD103 mAb dramatically attenuated CD8 infiltration into the renal tubules and tubular injury. Mouse studies documented that CD103 expression is required for efficient destruction of the graft renal tubules by CD8 effectors directed to donor MHC I alloantigens. Taken together, these data document a causal role for CD103+CD8+ effectors in promoting tubular injury following allogeneic renal transplantation and identify novel targets for therapeutic intervention in this important clinical problem.

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

“…There are some limitations to all these models, leaving open the question of whether the effector mechanisms are model specific, differing between islet and solid organ transplantation. A recent study (23) investigating the role of CD103 + CD8 + effector cells in rat kidney allografts, using a monoclonal antibody to CD103 to reduce accumulation of CD8 + cells in the graft, also concluded that CD103 was not essential for tubulitis or tubular injury, Histology, E-cadherin staining and tubular surface area in normal kidneys (NCBA), isografts and allografts rejecting in wild-type hosts (WT) or in hosts lacking granzyme A and B (GzmAB −/− ) or perforin (Prf −/− ) at day 21 1 1 E-cadherin staining was scored as the percentage of tubules in the cortex area with positive staining (<25%: 1; 25-75%: 2; >75%: 3); staining intensity was scored as weak (1), intermediate (2) or strong (3). Separate scores were obtained for staining of the basolateral or apical membrane.…”

“…+ effector cells in rat kidney allograft rejection found that treatment with a monoclonal antibody to CD103 reduced accumulation of CD8 + cells in graft renal tubules and attenuated tubular injury in cyclosporine-treated rats (23). In contrast, in rats with a fully functional immune system, i.e.…”

Integrin αE(CD103)β7 influences cellular shape and motility in a ligand-dependent fashion

“…Expression of ␣ E (CD103)␤ 7 appears to be associated with cytotoxic activity of CD8 ϩ T cells in graft-versus-host disease and allogeneic transplantation. 19,20 Along this line, interactions of ␣ E (CD103)␤ 7 with E-cadherin are crucial for lysis of E-cadherin ϩ tumor cells by cytotoxic T cells in some cases. 21 Moreover, expression of ␣ E (CD103)␤ 7 is associated with several important cellular activities such as antigen presentation 22 or stimulation of T reg 23 and some mucosal CD8 ϩ T cells 24,25 by ␣ E (CD103)␤ 7 ϩ dendritic cells.…”

Minimal Engagement of CD103 on Cytotoxic T Lymphocytes with an E-Cadherin-Fc Molecule Triggers Lytic Granule Polarization via a Phospholipase Cγ–Dependent Pathway

“…We previously reported that CD103 plays an essential role in TCR-dependent tumor-cell killing through interaction with its ligand, the epithelial cell marker E-cadherin on target cells (6). This integrin has also been associated with the cytotoxicity of CD8 þ T cells in several pathologies, including graft-versus-host disease (GVHD; 7), allogeneic transplant rejection (8)(9)(10), and autoimmune diseases (11,12). CD103 is frequently expressed on intraepithelial lymphocytes (IEL; 13) as well as on a subpopulation of CD3 þ / CD8 þ TIL (6,(14)(15)(16), CD4 þ /CD25 þ Treg cells (17), and dendritic cells (18).…”