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Thioredoxin-1 confines T cell alloresponse and pathogenicity in graft-versus-host disease
M. Hanief Sofi, … , Shikhar Mehrotra, Xue-Zhong Yu
M. Hanief Sofi, … , Shikhar Mehrotra, Xue-Zhong Yu
Published May 2, 2019
Citation Information: J Clin Invest. 2019;129(7):2760-2774. https://doi.org/10.1172/JCI122899.
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Research Article Immunology Article has an altmetric score of 29

Thioredoxin-1 confines T cell alloresponse and pathogenicity in graft-versus-host disease

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Abstract

Oxidative stress is elevated in the recipients of allogeneic hematopoietic cell transplantation (allo-HCT) and likely contributes to the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production, and migration of alloreactive donor T cells, and remains a major cause of morbidity and mortality after allo-HCT. Hence, strategies to limit oxidative stress in GVHD are highly desirable. Thioredoxin-1 (Trx1) counteracts oxidative stress by scavenging ROS and regulating other enzymes that metabolize H2O2. The present study sought to elucidate the role of Trx1 in the pathophysiology of GVHD. Using murine and xenograft models of allogeneic bone marrow transplantation (allo-BMT) and genetic (human Trx1-Tg) as well as pharmacological (human recombinant Trx1 [RTrx1]) strategies, we found that Trx1-Tg donor T cells or administration of RTrx1 to the recipients significantly reduced GVHD severity. Mechanistically, we observed that RTrx1 reduced ROS accumulation and cytokine production of mouse and human T cells in response to alloantigen stimulation in vitro. In allo-BMT settings, we found that Trx1-Tg or RTrx1 decreased downstream signaling molecules, including NF-κB activation and T-bet expression, and reduced proliferation, IFN-γ production, and ROS accumulation in donor T cells within GVHD target organs. More importantly, administration of RTrx1 did not impair the graft-versus-leukemia effect. Taken together, the current work provides a strong rationale for, and demonstrates the feasibility of, targeting the ROS pathway, which can be readily translated to the clinic.

Authors

M. Hanief Sofi, Yongxia Wu, Steven D. Schutt, Min Dai, Anusara Daenthanasanmak, Jessica Heinrichs Voss, Hung Nguyen, David Bastian, Supinya Iamsawat, Shanmugam Panneer Selvam, Chen Liu, Nilanjana Maulik, Besim Ogretmen, Junfei Jin, Shikhar Mehrotra, Xue-Zhong Yu

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Figure 4

Effect of Trx1 overexpression on donor T cell expansion and migration after allo-BMT.

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Effect of Trx1 overexpression on donor T cell expansion and migration af...
BMT was carried out as outlined in Figure 3 using BALB/c mice as the recipients. Three weeks after BMT, recipient spleens and livers were collected and mononuclear cells were isolated and subjected to cell counting and FACS staining. (A) CD98 expression is shown on live donor-derived (H2Kb+) CD4+ and CD8+ cells in 1 representative recipient. (B) The MFI of CD98 on donor-derived T cells is summarized in recipient spleen and liver, respectively. Data shown here are from 1 of 2 representative experiments. (C) CD4 and CD8 expression is shown on gated donor cells among live spleen or liver cells. IFN-γ, IL-4/5, and Foxp3 expression is shown on gated donor CD4+ cells from a representative mouse from each group. (D–G) The absolute numbers of IFN-γ+, IL-4/5+, or Foxp3+ donor (H2Kb+Ly5.1–) CD4+ (D and F) and CD8+ cells (E and G) in recipient spleen and liver, respectively. (H) CXCR3 expression is shown on donor-derived (H2Kb+) CD4+ cells in 1 representative recipient. (I) Percentage CXCR3+ cells is summarized on donor-derived CD4+ cells in recipient spleen. Data shown here are from 1 of 2 representative experiments. Significance was determined by Student’s t test. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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