Granzyme A Is Required for Regulatory T-Cell Mediated Prevention of Gastrointestinal Graft-versus-Host Disease

PLoS One. 2015 Apr 30;10(4):e0124927. doi: 10.1371/journal.pone.0124927. eCollection 2015.


In our previous work we could identify defects in human regulatory T cells (Tregs) likely favoring the development of graft-versus-host disease (GvHD) following allogeneic stem cell transplantation (SCT). Treg transcriptome analyses comparing GvHD and immune tolerant patients uncovered regulated gene transcripts highly relevant for Treg cell function. Moreover, granzyme A (GZMA) also showed a significant lower expression at the protein level in Tregs of GvHD patients. GZMA induces cytolysis in a perforin-dependent, FAS-FASL independent manner and represents a cell-contact dependent mechanism for Tregs to control immune responses. We therefore analyzed the functional role of GZMA in a murine standard model for GvHD. For this purpose, adoptively transferred CD4+CD25+ Tregs from gzmA-/- mice were analyzed in comparison to their wild type counterparts for their capability to prevent murine GvHD. GzmA-/- Tregs home efficiently to secondary lymphoid organs and do not show phenotypic alterations with respect to activation and migration properties to inflammatory sites. Whereas gzmA-/- Tregs are highly suppressive in vitro, Tregs require GZMA to rescue hosts from murine GvHD, especially regarding gastrointestinal target organ damage. We herewith identify GZMA as critical effector molecule of human Treg function for gastrointestinal immune response in an experimental GvHD model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / immunology
  • Disease Models, Animal
  • Gastrointestinal Diseases / genetics
  • Gastrointestinal Diseases / immunology*
  • Gastrointestinal Diseases / prevention & control*
  • Gene Expression
  • Graft vs Host Disease / genetics
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / prevention & control*
  • Granzymes / genetics
  • Granzymes / metabolism*
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Humans
  • Immunophenotyping
  • Immunotherapy, Adoptive
  • Lymphoid Tissue / immunology
  • Mice
  • Mice, Knockout
  • Phenotype
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*


  • Granzymes

Grant support

This work was supported by the German José Carreras leukemia foundation (grant DJCLS F12/05). JP was supported by ARAID foundation, grant SAF2011-25390 from Ministerio de Economia y Competitividad and Fondo Social Europeo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.