Bim regulates the survival and suppressive capability of CD8+ FOXP3+ regulatory T cells during murine GVHD

Abstract

CD8 Foxp3 T cells (Tregs) are a potent regulatory population whose functional and ontological similarities to CD4 Fox3 T cells have not been well delineated. Using an experimental model of graft-versus-host disease (GVHD), we observed that CD8 Tregs were significantly less potent than CD4 Tregs for the suppression of GVHD. To define the mechanistic basis for this observation, we examined the T-cell repertoire and the transcriptional profile of in vivo-derived CD4 and CD8 Tregs that emerged early during this disease. Polyclonal and alloantigen-induced CD8 Tregs had repertoire diversity that was similar to that of conventional CD8 T cells, indicating that a restricted repertoire was not the proximate cause of decreased suppression. Transcriptional profiling revealed that CD8 Tregs possessed a canonical Treg transcriptional signature that was similar to that observed in CD4 Tregs, yet distinct from conventional CD8 T cells. Pathway analysis, however, demonstrated that CD8 Tregs had differential gene expression in pathways involved in cell death and survival. This was further confirmed by detailed mRNA sequence analysis and protein expression studies, which demonstrated that CD8 Tregs had increased expression of Bim and reduced expression of Mcl-1. Transplantation with CD8 Foxp3 Bim Tregs resulted in prolonged Treg survival and reduced GVHD lethality compared with wild-type CD8 Tregs, providing functional confirmation that increased expression of Bim was responsible for reduced in vivo efficacy. Thus, Bim regulates the survival and suppressive capability of CD8 Tregs, which may have implications for their use in regulatory T-cell therapy.

Achievement of Tolerance Induction to Prevent Acute Graft-vs.-Host Disease

“…Although CD8+ iTregs expressed higher levels of suppressive molecules like CD39 + CD73 + , CTLA-4, and granzyme than CD4+ iTregs, there was no difference observed between their in vitro suppressive functions ( 82 ). In contrast to their in vitro suppressive functions, CD8+ iTregs are less potent than CD4+ iTregs in controlling GVHD due to their pro-apoptotic phenotype and thus reduced survival but are more effective in eliminating leukemia cells ( 82 , 225 ). Intriguingly, CD8+ iTreg expression of FoxP3 can be stabilized by JAK2 targeting ( 226 ).…”

CD8+ Tregs revisited: A heterogeneous population with different phenotypes and properties

“…Indeed, suppressive properties of CD8 + FOXP3 + T cells in vitro and in vivo have been documented by multiple studies in mice, human, and nonhuman primates [9‐15, 18]. A transcriptomic analysis showed that the gene expression profile of induced murine (m) CD8 + FOXP3 + Tregs is distinct from conventional CD8 + T cells, but similar to CD4 + Tregs [19]. Common phenotypic features of CD8 + FOXP3 + T cells and CD4 + Tregs include expression of CD25, CD103, GITR, CTLA‐4 in mice, as well as in human [12, 15, 20].…”

Blockade of miR-142-3p promotes anti-apoptotic and suppressive function by inducing KDM6A-mediated H3K27me3 demethylation in induced regulatory T cells

“…Both classes have the same CD4 + CD25 + CD127 low phenotype and express the transcription factor forkhead box P3 (FOXP3). Studies using preclinical models and clinical trials found that Tregs prevent autoimmune disease and graft-versus-host disease (GVHD) 2 . The shortage of tTregs impedes the development of Treg therapy 3 .…”