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-β dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-β 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-β–dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8+ T cells during GVHD pathogenesis.

Acute ischemic stroke is a leading cause of mortality and disability in the elderly. Age is the most important nonmodifiable risk factor for stroke, yet many preclinical models continue to examine only young male animals. It remains unclear how experimental stroke outcomes change with aging and with biologic sex. If sex differences are present, it is not known whether these reflect an intrinsic differing sensitivity to stroke or are secondary to the loss of estrogen with aging. We subjected both young and aging mice of both sexes to middle cerebral artery occlusion (MCAO). Young female mice had smaller strokes compared with age-matched males, an effect that was reversed by ovariectomy. Stroke damage increased with aging in female mice, whereas male mice had decreased damage after MCAO. Blood-brain barrier (BBB) permeability changes are correlated with infarct size. However, aging mice had significantly less edema formation, an effect that was independent of sex and histologic damage. Differences in the cellular response to stroke occur across the life span in both male and female mice. These differences need to be considered when developing relevant therapies for stroke patients, the majority of whom are elderly.

Background and Purpose-Over the past 5 years, experimental data have emerged that ischemia-induced cell death pathways may differ in males and females. Cell death in males is triggered by poly(ADP-ribose) polymerase activation and nuclear translocation of apoptosis-inducing factor. We have previously shown that interference with this pathway benefits males but not females after an experimental stroke. In contrast, caspase activation may be the major pathway activated after ischemic injury in females. The aim of this study is to examine whether sex differences exist in caspase activation in adult mice after stroke and to determine if interference with stroke-induced caspase activation preferentially protects females. Methods-Focal stroke was induced by reversible middle cerebral artery occlusion (90 minutes) in young and aging C57BL/6 mice of both sexes. The pan-caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy was administered at reperfusion. Histological outcomes were assessed 48 hours after middle cerebral artery occlusion. Separate cohorts were used for protein analysis of key cell death proteins, including caspase-3, caspase-8, cytochrome C, and apoptosisinducing factor. Results-Drug-treated female mice had significantly decreased infarct volumes and improved neurological deficits after stroke compared to vehicle-treated mice. Quinoline-Val-Asp(Ome)-CH2-O-phenoxy administration had no effect in male mice. The expression of cytochrome C and nuclear caspase-8 levels were increased in females after stroke. Conclusions-Female mice had an early release of cytochrome C and enhanced caspase activation after middle cerebral artery occlusion. Caspase inhibition benefited females but not males. Sex differences exist in both the response to ischemic injury and the efficacy of neuroprotective agents.

The mechanisms by which CD8 effector populations interact with epithelial layers is a poorly defined aspect of adaptive immunity. Recognition that CD8 effectors have the capacity to express CD103, an integrin directed to the epithelial cell-specific ligand E-cadherin, potentially provides insight into such interactions. To assess the role of CD103 in promoting CD8-mediated destruction of epithelial layers, we herein examined the capacity of mice with targeted disruption of CD103 to reject pancreatic islet allografts. Wild-type hosts uniformly rejected islet allografts, concomitant with the appearance of CD8+CD103+ effectors at the graft site. In contrast, the majority of islet allografts transplanted into CD103−/− hosts survived indefinitely. Transfer of wild-type CD8 cells into CD103−/− hosts elicited prompt rejection of long-surviving islet allografts, whereas CD103−/− CD8 cells were completely ineffectual, demonstrating that the defect resides at the level of the CD8 cell. CD8 cells in CD103−/− hosts exhibited normal effector responses to donor alloantigens in vitro and trafficked normally to the graft site, but strikingly failed to infiltrate the islet allograft itself. These data establish a causal relationship between CD8+CD103+ effectors and destruction of graft epithelial elements and suggest that CD103 critically functions to promote intragraft migration of CD8 effectors into epithelial compartments.