Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host disease
Sherrie J. Divito, … , Frode L. Jahnsen, Thomas S. Kupper
Sherrie J. Divito, … , Frode L. Jahnsen, Thomas S. Kupper
Published June 9, 2020
Citation Information: J Clin Invest. 2020;130(9):4624-4636. https://doi.org/10.1172/JCI129965.
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Research Article Immunology

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

Abstract

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.

Authors

Sherrie J. Divito, Anders T. Aasebø, Tiago R. Matos, Pei-Chen Hsieh, Matthew Collin, Christopher P. Elco, John T. O’Malley, Espen S. Bækkevold, Henrik 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, Jerome Ritz, Indira Guleria, Corey S. Cutler, Rachael A. Clark, Frode L. Jahnsen, Thomas S. Kupper

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Figure 2

Host T cells are present in skin during acute GVHD.

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Host T cells are present in skin during acute GVHD. (A) Example of FISH-...
(A) Example of FISH-IF from FFPE skin during acute GVHD. X chromosome, red; Y chromosome, green; CD3, yellow; DAPI nuclear stain, blue. Solid scale bar: 50 μm; dotted scale bar: 10 μm. Fine dotted line indicates dermal-epidermal junction. Pink arrow points to donor T cell; green arrow points to host T cell. (B) Percentage of host T cell chimerism in skin during acute GVHD, determined by FISH-IF. Solid red squares, all myeloablative-conditioned patients; open red squares, breakdown of myeloablative patients by conditioning regimen; solid black circles, all nonmyeloablative-conditioned patients; open black circles, breakdown of nonmyeloablative patients by conditioning regimen. Black lines indicate median. Mann-Whitney U test, 2-tailed, myeloablative vs. nonmyeloablative, P = 0.24, not significant. Myelo, myeloablative; Cy, cyclophosphamide; TBI, total body irradiation; Non-myelo, non-myeloablative; Mel, melphalan. (A and B) n = 26. (C) Example 5-color FISH-IF image from FFPE skin during acute GVHD. X chromosome, red; Y chromosome, green; CD3, yellow; CD4, magenta; DAPI nuclear stain, blue. Dotted white rectangle outlines region of enlarged images. Scale bars: 10 μm. Dotted gray circles outline CD3+CD4+ host T cells. n = 5. (D) Percentage of host T cell chimerism in skin, determined by FISH-IF, and blood, determined by STR analysis, at the time of acute GVHD. n = 17. Broken lines indicate paired specimens. Wilcoxon’s signed rank test, 2-tailed. ***P < 0.001.