Park, SungtaeGriesenauer, BradJiang, HuaAdom, DjamilatouMehrpouya-Bahrami, PegahChakravorty, SrishtiKazemian, MajidImam, TanbeenaSrivastava, RajneeshHayes, Tristan A.Pardo, JulianJanga, Sarath ChandraPaczesny, SophieKaplan, Mark H.Olson, Matthew R.2021-08-022021-08-022020-08-18Park, S., Griesenauer, B., Jiang, H., Adom, D., Mehrpouya-Bahrami, P., Chakravorty, S., Kazemian, M., Imam, T., Srivastava, R., Hayes, T. A., Pardo, J., Janga, S. C., Paczesny, S., Kaplan, M. H., & Olson, M. R. (2020). Granzyme A–producing T helper cells are critical for acute graft-versus-host disease. JCI Insight, 5(18). https://doi.org/10.1172/jci.insight.1244650021-9738https://hdl.handle.net/1805/26312Acute 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.en-USAttribution 4.0 InternationalImmunologyInflammationT cellsTh1 responseArticle