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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 6

STAT3 and STAT6 induce GrA+ Th cells’ differentiation and maintain lineage identity during GVHD.

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STAT3 and STAT6 induce GrA+ Th cells’ differentiation and maintain linea...
T cells isolated from mice from Figure 5 were analyzed for intracellular expression of GrA. (A) Representative FACS plots of intracellular GrA and CD4 expression from CD3+ cells isolated from LI, SI, and liver. (B) Quantification of the frequency of GrA+CD4+ T cells from the LI, SI, and liver. (C) Representative FACS plots of GrA and IFN-γ from CD4+ T cells isolated from LI and stimulated with PMA and ionomycin. (D) Quantification of the frequency of GrA+CD4+ T cells expressing IFN-γ. Data are pooled from 3 individual experiments where error bars represent standard deviation of the mean. Statistical significance was determined by 1-way ANOVA with Tukey’s posttest for multiple comparisons.
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