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Divito, Sherrie J; Aasebø, Anders T; Matos, Tiago R; Hsieh, Pei-Chen; Collin, Matthew; Elco, Christopher P; O'Malley, John T; Bækkevold, Espen S; Reims, Henrik; Gedde-Dahl, Tobias; Hagerstrom, Michael; Hilaire, Jude; Lian, John W; Milford, Edgar L; Pinkus, Geraldine S; Ho, Vincent T; Soiffer, Robert J; Kim, Haesook T; Mihm, Martin C; Ritz, Jerome; Guleria, Indira; Cutler, Corey S; Clark, Rachael A; Jahnsen, Frode L; Kupper, Thomas S
The Journal of clinical investigation, 09/2020, Volume: 130, Issue: 9Journal Article
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 proinflammatory cytokines IFN-γ and IL-17 in situ. Comparatively, the majority of antigen-presenting cells (APCs) in tissue in acute GVHD were donor derived, and donor-derived APCs 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.
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