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.

journal_name

Blood

journal_title

Blood

authors

Agle K,Vincent BG,Piper C,Belle L,Zhou V,Shlomchik W,Serody JS,Drobyski WR

doi

10.1182/blood-2017-09-807156

subject

Has Abstract

pub_date

2018-07-26 00:00:00

pages

435-447

issue

4

eissn

0006-4971

issn

1528-0020

pii

blood-2017-09-807156

journal_volume

132

pub_type

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