C/EBPβ Deletion Promotes Expansion of Poorly Functional Intestinal Regulatory T Cells.

Autor: Collins, Colm B, Puthoor, Pamela R, Nguyen, Tom T, Strassheim, Derek, Jedlicka, Paul, Friedman, Jacob E, Zoeten, Edwin F de
Zdroj: Journal of Crohn's & Colitis; Dec2018, Vol. 12 Issue 12, p1475-1485, 11p
Abstrakt: Background and Aims Inflammatory Bowel Diseases [IBDs] are chronic intestinal inflammatory conditions in part mediated by CD4+T cells. Anti-inflammatory Foxp3+regulatory T cells [Tregs] maintain immune homeostasis and protect against IBD development via multiple mechanisms, including cytokine secretion and cell–cell interaction. CCAAT enhancer binding protein-beta [C/EBPβ] is a stress-responsive transcription factor linked with IBD susceptibility. Whole-body C/EBPβ deficiency induces CD4+T cell–predominant hyperproliferation, and we hypothesize that this may be due to impaired Treg function. Methods We used the C/EBPβ–/–mice in the CD45RBHighadoptive transfer model, to assess C/EBPβ–/–CD4+T cells for their colitiogenic potential, and C/EBPβ–/–CD4+Foxp3+Tregs for their ability to inhibit colitis. We assessed Tregs from the C/EBPβ–/–mice for expression of Treg functional genes and proteins. Results Naïve C/EBPβ–/–CD4+T cells are more colitogenic in vivo. The exacerbated colitis does not appear to reflect impaired Treg development, however, as C/EBPβ–/–mice displayed more, rather than fewer intestinal CD4+Foxp3+Tregs in vivo. Instead, this reflects impaired Treg function as seen by the reduced capacity to suppress T cell proliferation in vitro, along with decreased secretion of the anti-inflammatory cytokine IL-10. These findings were corroborated in vivo by additional adoptive co-transfer studies in which wildtype Tregs prevented colitis but C/EBPβ–/–Tregs did not. Conclusion C/EBPβ deficiency impairs Treg function and potentiates T cell–mediated colitis. A clearer understanding of the function of this transcription factor may provide a novel therapeutic strategy for IBD. [ABSTRACT FROM AUTHOR]
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