TGF-{beta}-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease.
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-beta dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-beta 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-beta-dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8(+) T cells during GVHD pathogenesis.
El-Asady
Riham
R
Department of Surgery, University of Maryland Medical School, Baltimore, MD 21201, USA.
Yuan
Rongwen
R
Liu
Kechang
K
Wang
Donghua
D
Gress
Ronald E
RE
Lucas
Philip J
PJ
Drachenberg
Cinthia B
CB
Hadley
Gregg A
GA
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015820:Cadherins / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D039001:Integrin alpha Chains / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
D015703:Antigens, CD; D015820:Cadherins; D039001:Integrin alpha Chains; D011948:Receptors, Antigen, T-Cell; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C091367:alpha E integrins