doi:10.1172/jci.insight.124465engPark, 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.Granzyme A-producing T helper cells are critical for acute graft-versus-host diseaseART-2020-120192Acute 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.2020http://zaguan.unizar.es/record/9575410.1172/jci.insight.124465http://zaguan.unizar.es/record/95754oai:zaguan.unizar.es:95754info:eu-repo/grantAgreement/ES/DGA-FEDER/B29-17Rinfo:eu-repo/grantAgreement/ES/MCIU-AEI/SAF2017-83120-C2-1-RJCI insight 5, 18 (2020), e124465 [18 pp]byhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccess