Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing gata3 function

Deepali V. Sawant, Sarita Sehra, Evelyn T. Nguyen, Rohit Jadhav, Kate Englert, Ryo Shinnakasu, Giao Hangoc, Hal Broxmeyer, Toshinori Nakayama, Narayanan B. Perumal, Mark Kaplan, Alexander Dent

Research output: Contribution to journalArticle

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Abstract

The transcriptional repressor Bcl6 is a critical arbiter of Th cell fate, promoting the follicular Th lineage while repressing other Th cell lineages. Bcl6-deficient (Bcl6-/-) mice develop a spontaneous and severe Th2-type inflammatory disease, thus warranting assessment of Bcl6 in regulatory T cell (Treg) function. Bcl6-/- Tregs were competent at suppressing T cell proliferation in vitro and Th1-type colitogenic T cell responses in vivo. In contrast, Bcl6-/- Tregs strongly exacerbated lung inflammation in a model of allergic airway disease and promoted higher Th2 responses, including systemic upregulation of microRNA-21. Further, Bcl6-/- Tregs were selectively impaired at controlling Th2 responses, but not Th1 and Th17 responses, in mixed chimeras of Bcl6-/- bone marrow with Foxp3 -/- bone marrow. Bcl6-/- Tregs displayed increased levels of the Th2 transcription factor Gata3 and other Th2 and Treg genes. Bcl6 potently repressed Gata3 transcriptional transactivation, providing a mechanism for the increased expression of Th2 genes by Bcl6-/- Tregs. Gata3 has a critical role in regulating Foxp3 expression and functional fitness of Tregs; however, the signal that regulates Gata3 and restricts its transactivation of Th2 cytokines in Tregs has remained unexplored. Our results identify Bcl6 as an essential transcription factor regulating Gata3 activity in Tregs. Thus, Bcl6 represents a crucial regulatory layer in the Treg functional program that is required for specific suppression of Gata3 and Th2 effector responses by Tregs.

Original languageEnglish
Pages (from-to)4759-4769
Number of pages11
JournalJournal of Immunology
Volume189
Issue number10
DOIs
StatePublished - Nov 15 2012

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Regulatory T-Lymphocytes
Transcriptional Activation
Transcription Factors
Bone Marrow
T-Lymphocytes
Cell Lineage
MicroRNAs
Pneumonia
Up-Regulation
Cell Proliferation
Cytokines
Gene Expression
Genes
In Vitro Techniques

ASJC Scopus subject areas

  • Immunology

Cite this

Sawant, D. V., Sehra, S., Nguyen, E. T., Jadhav, R., Englert, K., Shinnakasu, R., ... Dent, A. (2012). Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing gata3 function. Journal of Immunology, 189(10), 4759-4769. https://doi.org/10.4049/jimmunol.1201794

Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing gata3 function. / Sawant, Deepali V.; Sehra, Sarita; Nguyen, Evelyn T.; Jadhav, Rohit; Englert, Kate; Shinnakasu, Ryo; Hangoc, Giao; Broxmeyer, Hal; Nakayama, Toshinori; Perumal, Narayanan B.; Kaplan, Mark; Dent, Alexander.

In: Journal of Immunology, Vol. 189, No. 10, 15.11.2012, p. 4759-4769.

Research output: Contribution to journalArticle

Sawant, DV, Sehra, S, Nguyen, ET, Jadhav, R, Englert, K, Shinnakasu, R, Hangoc, G, Broxmeyer, H, Nakayama, T, Perumal, NB, Kaplan, M & Dent, A 2012, 'Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing gata3 function', Journal of Immunology, vol. 189, no. 10, pp. 4759-4769. https://doi.org/10.4049/jimmunol.1201794
Sawant DV, Sehra S, Nguyen ET, Jadhav R, Englert K, Shinnakasu R et al. Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing gata3 function. Journal of Immunology. 2012 Nov 15;189(10):4759-4769. https://doi.org/10.4049/jimmunol.1201794
Sawant, Deepali V. ; Sehra, Sarita ; Nguyen, Evelyn T. ; Jadhav, Rohit ; Englert, Kate ; Shinnakasu, Ryo ; Hangoc, Giao ; Broxmeyer, Hal ; Nakayama, Toshinori ; Perumal, Narayanan B. ; Kaplan, Mark ; Dent, Alexander. / Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing gata3 function. In: Journal of Immunology. 2012 ; Vol. 189, No. 10. pp. 4759-4769.
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