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 6

Host skin T cells induce GVHD-like dermatitis independently of donor T cells in human skin–grafted mice.

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Host skin T cells induce GVHD-like dermatitis independently of donor T c...
(A) NSG mice were grafted with human skin and i.v. injected with saline, allogeneic monocytes alone, or allogeneic CD25-depleted PBMCs (labeled as PBMCs); skin grafts were studied after 3 weeks. (B) Mice injected with PBMCs developed a GVHD-like dermatitis characterized by acanthosis, parakeratosis, dyskeratosis, and lymphocytic infiltrates. (C) Monocyte-injected mice developed similar changes, including lymphocytic infiltrates (left panel), epidermal acanthosis and parakeratosis (middle panel), and basal layer vacuolization and destruction of rete ridges (right panel). (D) A second skin/blood pair with similar changes is shown. (B–D) Scale bars: 50 μm. (E) Histologic grading of GVHD-like dermatitis in skin grafts of monocyte- and PBMC-injected mice. (F and G) T cell numbers in skin, assessed by CD3E gene expression (F) and by HTS (G), were similar in monocyte- and PBMC-injected mice. (H) Host skin-resident T cells (TRM) proliferate after exposure to donor monocytes. The frequencies of the 20 most frequent T cell clones found in grafts from both saline- and monocyte-injected mice are shown. (I) Similar percentages of TRM clones proliferated in monocyte- and PBMC-injected mice. Histology and transcript analysis performed on saline-injected (n = 4), monocyte-injected (n = 9), and PBMC-injected (n = 7) mice. Clonality performed on monocyte-injected (n = 7) and PBMC-injected (n = 6) mice. (J) GVHD did not develop in the absence of host skin T cells. Mice grafted with human foreskin, which contains APC, but lacks T cells, and infused with PBMCs (n = 6) developed GVHD-like dermatitis, but monocyte-injected (n = 5) mice did not. Mean and SEM (error bars) are shown. Differences between 2 independent groups were detected using Mann-Whitney U test, 1-tailed. One-way Kruskal-Wallis test with Dunn’s post test was used for comparing multiple independent groups.