Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Granzyme A–producing T helper cells are critical for acute graft-versus-host disease
Sungtae Park, … , Mark H. Kaplan, Matthew R. Olson
Sungtae Park, … , Mark H. Kaplan, Matthew R. Olson
Published August 18, 2020
Citation Information: JCI Insight. 2020;5(18):e124465. https://doi.org/10.1172/jci.insight.124465.
View: Text | PDF
Research Article Immunology Inflammation

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

  • Text
  • PDF
Abstract

Acute graft-versus-host disease (aGVHD) can occur after hematopoietic cell transplant in patients undergoing treatment for hematological malignancies or inborn errors. Although CD4+ T helper (Th) cells play a major role in aGVHD, the mechanisms by which they contribute, particularly within the intestines, have remained elusive. We have identified a potentially novel subset of Th cells that accumulated in the intestines and produced the serine protease granzyme A (GrA). GrA+ Th cells were distinct from other Th lineages and exhibited a noncytolytic phenotype. In vitro, GrA+ Th cells differentiated in the presence of IL-4, IL-6, and IL-21 and were transcriptionally unique from cells cultured with either IL-4 or the IL-6/IL-21 combination alone. In vivo, both STAT3 and STAT6 were required for GrA+ Th cell differentiation and played roles in maintenance of the lineage identity. Importantly, GrA+ Th cells promoted aGVHD-associated morbidity and mortality and contributed to crypt destruction within intestines but were not required for the beneficial graft-versus-leukemia effect. Our data indicate that GrA+ Th cells represent a distinct Th subset and are critical mediators of aGVHD.

Authors

Sungtae Park, Brad Griesenauer, Hua Jiang, Djamilatou Adom, Pegah Mehrpouya-Bahrami, Srishti Chakravorty, Majid Kazemian, Tanbeena Imam, Rajneesh Srivastava, Tristan A. Hayes, Julian Pardo, Sarath Chandra Janga, Sophie Paczesny, Mark H. Kaplan, Matthew R. Olson

×

Figure 7

Th-derived GrA contributes to immunopathology during aGVHD.

Options: View larger image (or click on image) Download as PowerPoint
Th-derived GrA contributes to immunopathology during aGVHD.
(A) BALB/c m...
(A) BALB/c mice received syngeneic (Syn, n = 11) or C57BL/6 bone marrow with purified CD8+ and CD4+ T cells from WT or Gzma–/– C57BL/6 mice (WT CD4+/WT CD8+, n = 27; Gzma–/– CD4+/WT CD8+, n = 30; WT CD4+/Gzma–/– CD8+, n = 15). LI cells were harvested (at day 10 post-HCT) and assessed for GrA production by CD3+ cells by flow cytometry. Representative plots are gated on CD3+ cells (left panel), and the frequency of GrA+CD3+CD4+ T cells was quantified (right panel) based on the flow cytometry plots. Clinical scores and survival curves (B) from BALB/c recipient mice after HCT as per panel A. C3.SW-H2b/SnJ mice received bone marrow and T cells as per panel A. (C) Representative contour plots depict GrA+ T cells from the LI and the frequencies of GrA+CD4+ T cells in recipient mice isolated from the liver, SI, and LI. (D) Clinical scores and survival plot of C3.SW-H2b/SnJ that received WT (n = 14) or Gzma–/– CD4+ T cells (n = 14). Clinical score and survival plots represent pooled data across multiple experiments with mouse numbers indicated. Error bars represent standard deviation of the mean. *P < 0.05 by Student’s t test in B and D. Statistical significance in survival plots was performed by log-rank test (see Methods). One-way ANOVA with Tukey’s posttest was used to determine statistical significance in A and C.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts