Destruction of the host intestinal epithelium by donor effector T cell populations is a hallmark of graft-versus-host disease (GVHD), but the underlying mechanisms remain obscure. We demonstrate that CD8 T cells expressing CD103, an integrin conferring specificity for the epithelial ligand E-cadherin, play a critical role in this process. A TCR transgenic GVHD model was used to demonstrate that CD103 is selectively expressed by host-specific CD8 T cell effector populations (CD8 effectors) that accumulate in the host intestinal epithelium during GVHD. Although host-specific CD8 effectors infiltrated a wide range of host compartments, only those infiltrating the intestinal epithelium expressed CD103. Host-specific CD8 effectors expressing a TGF-dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-activity as a critical regulating factor. Host-specific CD8 effectors deficient in CD103 expression successfully migrated into the host intestinal epithelium but were retained at this site much less efficiently than wild-type host-specific CD8 effectors. The relevance of these events to GVHD pathogenesis is supported by the finding that CD103-deficient CD8 T cells were strikingly defective in transferring intestinal GVHD pathology and mortality. Collectively, these data document a pivotal role for TGF-–dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8 T cells during GVHD pathogenesis.

Graft-versus-host disease (GVHD) remains the primary complication of clinical BM transplantation (BMT) and a major impediment to the widespread application of this important therapeutic modality. The hallmark of GVHD is the infiltration of donor T lymphocytes into host epithelial compartments (1, 2) of the skin, intestine, and biliary tract (3). GVHD occurs when mature T cells contained in bone marrow inoculum are transplanted into immunoincompetent hosts. Donor T cells directed to host histocompatibility antigens are activated in secondary lymphoid organs (4) by encountering host APCs (3, 5) or donor-derived APCs which cross-present host alloantigens (6). The newly generated T effector populations then migrate to peripheral host organs (7) and mediate target organ damage.