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