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

Abstract

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.

Snai2 and Snai3 transcriptionally regulate cellular fitness and functionality of T cell lineages through distinct gene programs

“…However, this was not the case as the T Reg gene set was only enriched for the Cellular Compartment category of Extracellular Region (2.53-fold) that consisted of 34 genes, or approximately 9% of the total gene set (Figure 3G,H). However, this small cohort of targets included known T Reg effector molecules such as Il10 and Gzma [53, 54]. Il10 and Gzma were significantly reduced by 57% and 95%, respectively (Supplementary Table 5, Figure 6A,B shown are (left) UCSC genome browser tracks and (right) quantification of FPKM).…”

Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?

“…In direct contrast, however, Grossman et al demonstrated that nTregs stimulated with anti-CD3/CD28 and IL-2 upregulated the expression of GzmA, but not GzmB, and killed target cells via a perforin-dependent pathway (107). Currently, the reasons for this discrepancy are unknown and unresolved; in mice, GzmA, but not GzmB, contributes to Treg function during graft-versus-host disease (108, 109), raising the possibility that human Tregs may selectively express GzmA and GzmB selectively under specific circumstances.…”

Dynamic changes in the regulatory T cell heterogeneity and function by murine IL-2 mutein

“…2E and 3C, Fig. S6B and S9A), while C5 Tregs 10 express effectors that promotes suppression (C5: Il10(38), Gzma (39) and Gzmb (40,41)) or tissue protection (C5: Areg(42)) ( Fig. 2E and 3C, Fig.…”