Granzyme A Is Required for Regulatory T-Cell Mediated Prevention of Gastrointestinal Graft-versus-Host Disease.
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.
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Sarvari
S
Velaga
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Sya N
SN
Ukena
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Ulrike
U
Dringenberg
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Christina
C
Alter
Immune Effector Cells Group (ICE), Biomedical Research Centre of Aragon (CIBA), Zaragoza, Spain.
Julian
J
Pardo
Department of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
Olivia
O
Kershaw
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Anke
A
Franzke
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D004195:Disease Models, Animal; D005767:Gastrointestinal Diseases / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
D053804:Granzymes