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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 4

IL-6/21 alters the IL-4–induced transcriptional program and promotes Gzma production.

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IL-6/21 alters the IL-4–induced transcriptional program and promotes Gzm...
(A) Heatmap of statistically significant (FDR < 0.05; fold change > 2) gene expression of cells cultured under Th0, Th0+IL-6/21 (IL-6/21), Th0+IL-4 (IL-4), or Th0+IL-4+IL-6/21 (IL-4+IL-6/21) based on a 2-fold change cutoff. Data represent the means expression from cells isolated from 3 animals per condition. (B) Number of up- or downregulated genes as compared with Th0 cells. (C) Select genes from the subset of genes that are uniquely enriched in cells cultured with IL-4+IL-6/21. (D) Verification of Gzma expression via real-time PCR. (E) mRNA expression levels in cells isolated from C57BL/6 Stat3fl/fl Cd4-Cre– (WT) and Stat3fl/fl Cd4-Cre+ mice and (F) WT and Stat6–/– mice (BALB/c) after culture with IL-4+IL-6/21. Experiments from E and F are representative of 2 individual experiments with cells isolated from 2–3 mice per experiment. Error bars represent standard deviation of the mean. Statistical significance was determined by Student’s t test.

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