Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host disease
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
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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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 4

Acute GVHD affects host T cell chimerism in skin.

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Acute GVHD affects host T cell chimerism in skin. (A) Percentage of host...
(A) Percentage of host T cell chimerism as quantified by sequential FISH-IF on cytospins of skin migratory cells at 40, 100, and 365 days after transplant. Open black circles, no GVHD; open red circles, active acute skin GVHD at time of biopsy; closed red circles, active acute skin GVHD and prior history of active acute skin GVHD; closed black circles, history of acute skin GVHD resolved at time of biopsy. Black lines indicate median. Dunn’s multiple comparison’s test for no GVHD 40 vs. 100 days. P > 0.05, not significant. (B) FISH-IF data for individual patients depicted in pie charts (gold, host; blue, donor) at 40, 100, and/or 365 days after transplant. Red plus sign indicates active acute skin GVHD at time of biopsy. Red bars indicate prior history of acute skin GVHD. Open bars indicate no prior history of acute skin GVHD. (C) Representative FISH-IF of a female patient transplanted with a male donor, skin sample taken at 40 days after transplant. This patient had a prior history of acute skin GVHD resolved at time of biopsy. Staining was performed as follows: HLA-DR, green; CD14, red; CD3 and factor XIIIA, both blue (easily discernible by morphology); FISH, X chromosomes, pink; Y chromosomes, green. Montages of corresponding FISH images are outlined with gray dotted squares. Quantification yielded host T cell chimerism of 87% and myeloid cell (HLA-DR+CD14+) chimerism of 98% donor. Asterisks, host (XX) T cells; white arrowhead, donor (XY) T cell; blue arrowheads, CD3+ T cells; M, macrophage. Scale bar: 20 μm. (A–C) n = 34.