Eos Mediates Foxp3-Dependent Gene Silencing in CD4⁺ Regulatory T Cells

Fan Pan,¹ Hong Yu,¹ Eric V. Dang,¹ Joseph Barbi,¹ Xiaoyu Pan,¹ Joseph F. Grosso,¹ Dinili Jinasena,¹ Sudarshana M. Sharma,² Erin M. McCadden,¹ Derese Getnet,¹ Charles G. Drake,¹ Jun O. Liu,³ Michael C. Ostrowski,² Drew M. Pardoll^1,*

Abstract: CD4⁺ regulatory T cells (T_regs) maintain immunological self-tolerance and immune homeostasis by suppressing aberrant or excessive immune responses. The core genetic program of T_regs and their ability to suppress pathologic immune responses depends on the transcription factor Foxp3. Despite progress in understanding mechanisms of Foxp3-dependent gene activation, the molecular mechanism of Foxp3-dependent gene repression remains largely unknown. We identified Eos, a zinc-finger transcription factor of the Ikaros family, as a critical mediator of Foxp3-dependent gene silencing in T_regs. Eos interacts directly with Foxp3 and induces chromatin modifications that result in gene silencing in T_regs. Silencing of Eos in T_regs abrogates their ability to suppress immune responses and endows them with partial effector function, thus demonstrating the critical role that Eos plays in T_reg programming.

¹ Immunology and Hematopoiesis Division, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
² Department of Molecular and Cellular Biochemistry and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
³ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

^* To whom correspondence should be addressed. E-mail: dpardol1{at}jhmi.edu

GPR15-Mediated Homing Controls Immune Homeostasis in the Large Intestine Mucosa.

S. V. Kim, W. V. Xiang, C. Kwak, Y. Yang, X. W. Lin, M. Ota, U. Sarpel, D. B. Rifkin, R. Xu, and D. R. Littman (2013)
Science
 |  Abstract »

Cutting Edge: A Novel, Human-Specific Interacting Protein Couples FOXP3 to a Chromatin-Remodeling Complex That Contains KAP1/TRIM28.

C. Huang, S. Martin, C. Pfleger, J. Du, J. H. Buckner, J. A. Bluestone, J. L. Riley, and S. F. Ziegler (2013)
J. Immunol. 190, 4470-4473
 |  Abstract »  |  Full Text »  |  PDF »

Helios Induces Epigenetic Silencing of Il2 Gene Expression in Regulatory T Cells.

I. Baine, S. Basu, R. Ames, R. S. Sellers, and F. Macian (2013)
J. Immunol. 190, 1008-1016
 |  Abstract »  |  Full Text »  |  PDF »

IL-10 Produced by Induced Regulatory T Cells (iTregs) Controls Colitis and Pathogenic Ex-iTregs during Immunotherapy.

E. G. Schmitt, D. Haribhai, J. B. Williams, P. Aggarwal, S. Jia, L.-M. Charbonnier, K. Yan, R. Lorier, A. Turner, J. Ziegelbauer, et al. (2012)
J. Immunol. 189, 5638-5648
 |  Abstract »  |  Full Text »  |  PDF »

CD147 (Basigin/Emmprin) identifies FoxP3+CD45RO+CTLA4+-activated human regulatory T cells.

T. Solstad, S. J. Bains, J. Landskron, E. M. Aandahl, B. Thiede, K. Tasken, and K. M. Torgersen (2011)
Blood 118, 5141-5151
 |  Abstract »  |  Full Text »  |  PDF »

Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease.

J. VanValkenburgh, D. I. Albu, C. Bapanpally, S. Casanova, D. Califano, D. M. Jones, L. Ignatowicz, S. Kawamoto, S. Fagarasan, N. A. Jenkins, et al. (2011)
J. Exp. Med. 208, 2069-2081
 |  Abstract »  |  Full Text »  |  PDF »

Connexin 43 Signaling Enhances the Generation of Foxp3+ Regulatory T Cells.

M. Kuczma, J. R. Lee, and P. Kraj (2011)
J. Immunol. 187, 248-257
 |  Abstract »  |  Full Text »  |  PDF »

The Yin and Yang of Signaling in Tregs and TH17 Cells.

F. Pan, H. Fan, L. Lu, Z. Liu, and S. Jiang (2011)
Science Signaling 4, mr4
 |  Abstract »  |  Full Text »  |  PDF »

Expression of Helios, an Ikaros Transcription Factor Family Member, Differentiates Thymic-Derived from Peripherally Induced Foxp3+ T Regulatory Cells.

A. M. Thornton, P. E. Korty, D. Q. Tran, E. A. Wohlfert, P. E. Murray, Y. Belkaid, and E. M. Shevach (2010)
J. Immunol. 184, 3433-3441
 |  Abstract »  |  Full Text »  |  PDF »