Target cells in graft-versus-host disease: implications for cancer therapy

Acute graft-versus-host disease (GVHD) conceptually may be divided into three evolutionary stages: allostimulation, effector cell homing to specific tissues, and cellular targeting and injury. Surprisingly, little is known regarding the targeting stage of GVHD. Recently, we have learned that epithelial target cell injury is mediated by specific subpopulations of effector T cells that may be identified based on Vbeta family expansion during allostimulation. Antibody probes specific for these Vbeta families have permitted precise identification of effector cell homing patterns. In squamous epithelium, allospecific T cells selectively home to basal cell layer subpopulations that express cytokeratin 15 (CK15) and that undergo target cell injury via apoptosis. Interestingly, these target cells coincide with basal layer subpopulations that have properties of epithelial stem cells and that normally express an apoptosis-resistant genomic profile. Accordingly, epithelial cell injury in GVHD appears to involve selective targeting of stem-cell subpopulations via conversion from an anti-apoptotic to a pro-apoptotic phenotype. Understanding of the mechanism(s) of this conversion could facilitate development of translationally relevant approaches to shielding target cells from injury in GVHD. Moreover, determination of how putative apoptosis-resistant stem cells may be rendered vulnerable to immune-mediated targeting has implications potentially relevant to more directed immunotherapeutic approaches focused at elimination of neoplastic (cancer) stem cells.