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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.
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Research Article Immunology Inflammation

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

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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

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Figure 8

Th cell–derived GrA is not required for the beneficial GVL effect of HCT.

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Th cell–derived GrA is not required for the beneficial GVL effect of HCT...
Lethally irradiated BALB/c mice received 104 GFP+ MLL-AF9 leukemia cells, bone marrow, and T cells from syngeneic controls or allo-HCTs from C57BL/6 mice with WT T cells, Gzma–/– T cells, or Gzma–/– CD4+ T cells and WT CD8+ T cells. After transplant, mice were monitored for clinical score (A) and mortality (B). (C) At a predetermined clinical endpoint (or selected as controls if mice did not reach the clinical endpoint), mice were euthanized, and the frequency of GFP+ MLL-AF9 cells was quantified in the bone marrow by flow cytometry. The percentages of mice that succumbed to leukemia or GVHD (D) were determined based on clinical score and the frequency of GFP+ MLL-AF9 cells present in the bone marrow as per panels A and C. Error bars represent standard error of the mean in panel A from 12 mice per group and the standard deviation in panel C from the number of mice indicated. Statistical difference in survival plots was performed by log-rank test (see Methods) and for frequency of GFP+ cells by 2-way ANOVA with Holm-Šidák correction for multiple comparisons.
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