Selective destruction of the host intestinal epithelium by CD8 T effector populations is a hallmark of graft-versus-host disease (GVHD) pathology, but the underlying mechanisms remain enigmatic. The intestinal epithelium is associated with high levels of TGF-beta, known to induce expression of CD103, a T cell integrin conferring specificity for the epithelial ligand E-cadherin. The goal of this study was to determine if CD103 is expressed by CD8 cells that infiltrate host epithelial compartments during GHVD and if so, whether such expression promotes interaction of alloreactive CD8 effectors with epithelial targets. To induce GVHD, lethally irradiated Balb/c (L d+) hosts were transplanted with bone marrow and spleen cells from C57BL/6 (B6) mice (H-2b) in combination with small numbers of CD8+ T cells from 2C TCR-transgenic (Ld-specific) mice (H-2b). The use of a mAb to the 2C TCR (1B2) in FACS analyses allowed tracking of a host-specific CD8 effector (hsCD8eff) population during GVHD. Strikingly, hsCD8eff infiltrating the intestinal epithelium progressively upregulated CD103 expression, while hsCD8eff infiltrating other host compartments, such as the kidney, spleen and liver, remained CD103- at all time points. HsCD8eff expressing a dominant-negative TGF-beta receptor were defective in this regard, implicating TGF-beta as a dominant controlling factor. Furthermore, induction of local TGF-beta activity in the kidney, by inflicting ischemia reperfusion injury (IRI), was associated with upregulation of CD103 by hsCDeff infiltrating the renal milieu in a TGF-beta-dependent manner. HsCD8eff infiltrating other compartments following IRI of the kidney, however, did not express CD103, providing compelling evidence that local TGF-beta activity at peripheral sites of inflammation is critical in the regulation of CD103 by alloreactive CD8 effectors. Studies with CD 103-/- hsCD8eff revealed that CD 103 expression is not required for initial migration of hsCD8eff into the intestinal epithelium, but is necessary for efficient retention in this compartment. The relevance of these events to GVHD pathogenesis is supported by the finding that CD103-deficient CD8 + T cells are strikingly defective in transferring intestinal GVHD pathology and mortality. Collectively, these data document a pivotal role for TGF-beta-dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8+ T cells during GVHD pathogenesis.