Graft-versus-host-disease (GVHD) is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Donor T cells are key mediators in pathogenesis but a contribution from host T cells has not been explored, as conditioning regimens are believed to deplete host T cells. To evaluate a potential role for host T cells in GVHD, the origin of skin and blood T cells was assessed prospectively in patients after HSCT in the absence of GVHD. While blood contained primarily donor-derived T cells, most T cells in the skin were host-derived. We next examined patient skin, colon and blood during acute GVHD. Host T cells were present in all skin and colon acute GVHD specimens studied yet were largely absent in blood. We observed acute skin GVHD in the presence of 100% host T cells. Analysis demonstrated that a subset of host T cells in peripheral tissues were proliferating (Ki67+) and producing the pro-inflammatory cytokines IFNγ and IL-17 in situ. Comparatively, the majority of antigen presenting cells (APC) in tissue in acute GVHD were donor-derived, and donor-derived APC were observed directly adjacent to host T cells. A humanized mouse model demonstrated that host skin-resident T cells could be activated by donor monocytes to generate a GVHD-like dermatitis. Thus, host tissue-resident T cells may play a previously unappreciated pathogenic role in acute GVHD.
Sherrie J. Divito, Anders T. Aasebo, Tiago R. Matos, Pei-Chen Hsieh, Matthew Collin, Christopher P. Elco, John T. O'Malley, Espen S. Bækkevold, Henrik M. Reims, Tobias Gedde-Dahl, Michael Hagerstrom, Jude Hilaire, John W. Lian, Edgar L. Milford, Geraldine S. Pinkus, Vincent T. Ho, Robert J. Soiffer, Haesook T. Kim, Martin C. Mihm Jr, Jerome Ritz, Indira Guleria, Corey S. Cutler, Rachael Clark, Frode L. Jahnsen, Thomas S. Kupper