Granzyme A-producing T helper cells are critical for acute graft-versus-host disease

JCI Insight. 2020 Sep 17;5(18):e124465. doi: 10.1172/jci.insight.124465.


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.

Keywords: Immunology; Inflammation; T cells; Th1 response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Graft vs Host Disease / etiology
  • Graft vs Host Disease / metabolism
  • Graft vs Host Disease / pathology*
  • Graft vs Leukemia Effect / immunology*
  • Granzymes / physiology*
  • Hematologic Neoplasms / therapy
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Intestines / immunology
  • Intestines / pathology*
  • Lymphocyte Activation / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • STAT3 Transcription Factor / physiology
  • STAT6 Transcription Factor / physiology
  • T-Lymphocytes, Helper-Inducer / immunology*


  • STAT3 Transcription Factor
  • STAT6 Transcription Factor
  • Stat3 protein, mouse
  • Stat6 protein, mouse
  • Granzymes
  • granzyme A, mouse