The Impact of Cell-Intrinsic STAT6 Protein on Donor T Cell-Mediated Graft-Versus-Tumor Effect

Xiaoqun Guan; Hope Fury; Priya D. Issuree; Tyler Atagozli; Emory E. McManimon; Peng Shao; Yue Li; Michael Chimenti; Noah S. Butler; Mark H. Kaplan; David E. Elliott; Bruce R. Blazar; M. Nedim Ince

doi:10.3390/ijms26010280

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The Impact of Cell-Intrinsic STAT6 Protein on Donor T Cell-Mediated Graft-Versus-Tumor Effect

Journal article

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The Impact of Cell-Intrinsic STAT6 Protein on Donor T Cell-Mediated Graft-Versus-Tumor Effect

Xiaoqun Guan, Hope Fury, Priya D. Issuree, Tyler Atagozli, Emory E. McManimon, Peng Shao, Yue Li, Michael Chimenti, Noah S. Butler, Mark H. Kaplan, …

International journal of molecular sciences, Vol.26(1), 280

12/31/2024

DOI: 10.3390/ijms26010280

PMCID: PMC11719522

PMID: 39796136

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Abstract

Bone marrow transplantation (BMT) is mainly performed to restore an anti-tumor immune response, called the graft-versus-tumor (GVT) effect, against leukemia, myeloma and lymphoma. This GVT reactivity is driven by donor T cells, and it can also cause lethal graft-versus-host disease (GVHD). We previously demonstrated that the colonization of mice with helminths preserves the GVT response while suppressing GVHD. As the T helper-2 (Th2) pathway is critical to helminthic immune regulation, we asked whether the genetic induction of Th2 signaling in donor T cells can restore helminthic immune regulation after BMT. Our studies utilized transgenic donor T lymphocytes that overexpress a constitutively active form of the Th2-associated transcription factor STAT6. Constitutively active STAT6 sustained the GVT response without causing severe acute GVHD, where transgenic T cells generated robust quantities of cytotoxic proteins important in GVT response, such as granzymes A and B, interferon-γ and Fas ligand, in addition to generating high quantities of Th2/regulatory cytokines. Bioinformatic analysis based on chromosome immune precipitation experiments indicated that STAT6 stimulates the expression of granzymes directly. Thus, in preserving the GVT response without causing GVHD mortality, our results indicate the therapeutic potential of restoring helminthic immune modulation by targeting STAT6 and STAT6-dependent T cell maturation.

STAT6

T helper-2

graft-versus-host disease

graft-versus-tumor effect

bone marrow transplantation

granzyme A

granzyme B

Details

Title: Subtitle: The Impact of Cell-Intrinsic STAT6 Protein on Donor T Cell-Mediated Graft-Versus-Tumor Effect
Creators: Xiaoqun Guan - University of Iowa
Hope Fury - University of Iowa
Priya D. Issuree - University of Iowa, Infectious Diseases
Tyler Atagozli - University of Iowa
Emory E. McManimon - University of Iowa
Peng Shao - University of Iowa
Yue Li - University of Iowa
Michael Chimenti - University of Iowa
Noah S. Butler - University of Iowa
Mark H. Kaplan - Indiana University
David E. Elliott - University of Iowa
Bruce R. Blazar - University of Minnesota
M. Nedim Ince - University of Iowa, Gastroenterology and Hepatology
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.26(1), 280
DOI: 10.3390/ijms26010280
PMID: 39796136
PMCID: PMC11719522
NLM abbreviation: Int J Mol Sci
ISSN: 1422-0067
eISSN: 1422-0067
Publisher: MDPI; BASEL
Grant note: U.S. Department of Veterans Affairs Merit Award
This study is funded by the U.S. Department of Veterans Affairs Merit Award, 2I01BX002906.
Language: English
Date published: 12/31/2024
Academic Unit: Molecular Physiology and Biophysics; Microbiology and Immunology; Infectious Diseases; Gastroenterology and Hepatology; Biology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984770792002771

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