Acute graft-versus-host disease (a-GVHD) is initiated primarily by immunologically competent cytotoxic T cells (CTLs) that express anti-host specificities. However, the host lymphoid compartment in which these precursor CTLs are initially stimulated remains unclear. Here we show that gut Peyer's patches (PPs) are required to activate anti-host CTL responses in a well characterized murine acute graft-versus-host reaction (a-GVHR) model, involving transfer of parent lymphocytes into F1 hybrid recipients. The a-GVHR was prevented when recruitment of donor T cells into PP was interrupted either by disrupting the gene encoding chemokine receptor CCR5 or by blocking integrin α4β7–MAdCAM-1 (mucosal vascular addressin) interactions. Mice deficient for PPs failed to develop a-GVHD in two models of disease induction. Thus, blockade of CTL generation in PPs might offer new strategies for circumventing a-GVHD.
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We thank J.J. Oppenheim, K. Matsuno, S. Ishikawa, M. Haino and C. Vestergaard for helpful discussions and S. Fujita for assistance in animal surgery. This work was supported by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists (M.M.), by Grant-in-Aid for Creative Scientific Research, the Japan Society for the Promotion of Science (13GS0015) and Special Coordination Fund for Promoting Science and Technology, Ministry of Education, Culture, Sport, Science and Technology (H.I.) and by a grant from Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Corporation (K.M.).
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