The Journal of Experimental Medicine
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Published 16 May 2005. doi:10.1084/jem.20041044
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 10, 1647-1657
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ARTICLE

 TGF-ß–dependent CD103 expression by CD8+ T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease

Riham El-Asady2, Rongwen Yuan1, Kechang Liu2, Donghua Wang1, Ronald E. Gress4, Philip J. Lucas4, Cinthia B. Drachenberg3, and Gregg A. Hadley1,2

1 Department of Surgery, University of Maryland Medical School, Baltimore, MD 21201
2 Department of Microbiology and Immunology, University of Maryland Medical School, Baltimore, MD 21201
3 Department of Pathology, University of Maryland Medical School, Baltimore, MD 21201
4 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

CORRESPONDENCE Gregg A. Hadley: ghadley{at}smail.umaryland.edu

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

Abbreviations used: B6, C57BL/6; BMC, BM cells; BMT, BM transplantation; CD8 effectors, CD8+ T cell effector populations; CFSE, carboxy- fluorescein diacetate succinimidyl ester; DNR, dominant negative TGF-ß type II receptor; GVHD, graft-versus-host disease; H&E, hematoxylin and eosin; hsCD8eff, host-specific CD8 effectors; MLN, mesenteric LNs; MST, mean survival time; SC, spleen cells; TCR-Tg, TCR transgenic.


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