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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 1

GrA+ Th cells are a hallmark of intestinal GVHD and represent a distinct Th subset.

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GrA+ Th cells are a hallmark of intestinal GVHD and represent a distinct...
Irradiated BALB/c mice received syngeneic (BALB/c→BALB/c) or allogeneic (C57BL/6→BALB/c) bone marrow and T cells. After transplant (day 10), small intestine (SI) and large intestine (LI) tissue were collected from 3 animals per group for RNA analysis (A), or spleen, liver, SI, and LI were harvested for cellular GrA analysis by flow cytometry (B). (C and D) The frequency of GrA+CD8+ T cells (CD3+CD4–) or CD4+ T cells (CD3+CD4+) in each tissue from 5–16 syngeneic mice and 14–33 allogeneic mice. (D) Percentages of intestinal GrA+ Th cells. Left panel, representative plots of GrA and CD3 staining. Right panel, the frequency of CD4+ and CD8+ T cells within GrA+ cells from various organs. *P < 0.05 (Student’s t test) as compared with frequency of cells in spleen. (E) GrB and FOXP3 expression (unstimulated) and IL-17A and IFN-γ expression (stimulated) by intestinal Th cells from allogeneic mice. Cellular analysis is representative of 4 experiments with 3 mice per group and error bars represent standard deviation of the mean. (F) CyTOF analysis of intestinal Th cells, pooled from 10 mice, at day 10 after allogeneic transplant. t-Distributed stochastic neighbor embedding (t-SNE) dimensionality reduction plots represent expression data from GrA, IFN-γ, TNF, and IL-2 staining.

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