Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host disease

• Published in: The Journal of clinical investigation Vol. 130; no. 9; pp. 4624 - 4636
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2020
• Subjects: Adult; Allografts; Animals; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - pathology; Female; Graft vs Host Disease - immunology; Graft vs Host Disease - pathology; Health aspects; Hematopoietic Stem Cell Transplantation; Humans; Interferon-gamma - immunology; Interleukin-17 - immunology; Male; Medical research; Mice; Mice, Inbred NOD; Mice, SCID; Prospective Studies; Scientific equipment industry; Skin; Skin - immunology; Skin - pathology; Skin Diseases - immunology; Skin Diseases - pathology; Stem cells; T cells; T-Lymphocytes - immunology; T-Lymphocytes - pathology; United States; Norway; Massachusetts; Bone marrow transplantation; Transplantation; Immunology; T cells
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI129965

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.