Visual AbstractAbstract

IL-9, produced mainly by specialized T cells, mast cells, and group 2 innate lymphoid cells, regulates immune responses, including anti-helminth and allergic responses. Polarization of naive CD4 T cells into IL-9–producing T cells (Th9s) is induced by IL-4 and TGF-β1 or IL-1β. In this article, we report that the transcription factor growth factor–independent 1 transcriptional repressor (GFI1) plays a negative role in mouse Th9 polarization. Moreover, the expression of GFI1 is controlled by liganded RARα, allowing GFI1 to mediate the negative effect of retinoic acid on IL-9 expression. The Gfi1 gene has multiple RARα binding sites in the promoter region for recruiting nuclear coactivator steroid receptor coactivator-3 and p300 for histone epigenetic modifications in a retinoic acid–dependent manner. Retinoic acid–induced GFI1 binds the Il9 gene and suppresses its expression. Thus, GFI1 is a novel negative regulator of Il9 gene expression. The negative GFI1 pathway for IL-9 regulation provides a potential control point for Th9 activity.

Footnotes

This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) (Grants R21AI14889801, R01AI074745, and 1R01AI080769 to C.H.K.) and National Institute of Allergy, NIH (Grant R01AI121302 to C.H.K.).

The online version of this article contains supplemental material.

L.F., R.K., and Q.L. carried out experiments and plotted the data. L.F. and H.Y. analyzed the RNA sequencing data. J.Z. provided Gfi1−/−mice, and N.L. provided expertise in interpretation of the lung data. C.H.K. conceived and directed the study, obtained funding, and drafted the manuscript. All participated in making the final manuscript for submission.

Abbreviations used in this article:

ChIPchromatin immunoprecipitationChIP-seqchromatin immunoprecipitation sequencingGFI1growth factor–independent 1 transcriptional repressorhhumanKORara knockoutmmouseRAall-trans retinoic acidRAREretinoic acid response elementRNA-seqRNA sequencingSRC3steroid receptor coactivator-3TGRaraα-transgenicTh9IL-9–producing T cellTregregulatory T cellWTwild-typeReceived May 6, 2022.Accepted August 7, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.