Bim regulates the survival and suppressive capability of CD8<superscript>+</superscript> FOXP3<superscript>+</superscript> regulatory T cells during murine GVHD.
In: Blood, Jg. 132 (2018-07-26), Heft 4, S. 435-447
academicJournal
Zugriff:
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. [ABSTRACT FROM AUTHOR]
Titel: |
Bim regulates the survival and suppressive capability of CD8<superscript>+</superscript> FOXP3<superscript>+</superscript> regulatory T cells during murine GVHD.
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Autor/in / Beteiligte Person: | Agle, Kimberle ; Vincent, Benjamin G. ; Piper, Clint ; Belle, Ludovic ; Zhou, Vivian ; Shlomchik, Warren ; Serody, Jonathan S. ; Drobyski, William R. |
Zeitschrift: | Blood, Jg. 132 (2018-07-26), Heft 4, S. 435-447 |
Veröffentlichung: | 2018 |
Medientyp: | academicJournal |
ISSN: | 0006-4971 (print) |
DOI: | 10.1182/blood-2017-09-807156 |
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