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

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Abstract

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 CD45RBHigh adoptive 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.

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Collins, C. B., Puthoor, P. R., Nguyen, T. T., Strassheim, D., Jedlicka, P., Friedman, J. E., & De Zoeten, E. F. (2018). C/EBPβ Deletion Promotes Expansion of Poorly Functional Intestinal Regulatory T Cells. Journal of Crohn’s and Colitis, 12(12), 1475–1485. https://doi.org/10.1093/ecco-jcc/jjy105

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