Analysis of Interleukin-21-induced Prdm1 Gene Regulation Reveals Functional Cooperation of STAT3 and IRF4 Transcription Factors

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2010 Jan 13

PMID 20064451

Citations 214

Authors

Hyokjoon Kwon

Danielle Thierry-Mieg

Jean Thierry-Mieg

Hyoung-Pyo Kim

Jangsuk Oh

Chainarong Tunyaplin

Sebastian Carotta

Colleen E Donovan

Matthew L Goldman

Prafullakumar Tailor

Keiko Ozato

David E Levy

Stephen L Nutt

Kathryn Calame

Warren J Leonard

Affiliations

Soon will be listed here.

Abstract

Interleukin-21 (IL-21) is a pleiotropic cytokine that induces expression of transcription factor BLIMP1 (encoded by Prdm1), which regulates plasma cell differentiation and T cell homeostasis. We identified an IL-21 response element downstream of Prdm1 that binds the transcription factors STAT3 and IRF4, which are required for optimal Prdm1 expression. Genome-wide ChIP-Seq mapping of STAT3- and IRF4-binding sites showed that most regions with IL-21-induced STAT3 binding also bound IRF4 in vivo and furthermore revealed that the noncanonical TTCnnnTAA GAS motif critical in Prdm1 was broadly used for STAT3 binding. Comparing genome-wide expression array data to binding sites revealed that most IL-21-regulated genes were associated with combined STAT3-IRF4 sites rather than pure STAT3 sites. Correspondingly, ChIP-Seq analysis of Irf4(-/-) T cells showed greatly diminished STAT3 binding after IL-21 treatment, and Irf4(-/-) mice showed impaired IL-21-induced Tfh cell differentiation in vivo. These results reveal broad cooperative gene regulation by STAT3 and IRF4.

Citing Articles

The multiple roles of interferon regulatory factor family in health and disease.

Wang L, Zhu Y, Zhang N, Xian Y, Tang Y, Ye J Signal Transduct Target Ther. 2024; 9(1):282.

PMID: 39384770 PMC: 11486635. DOI: 10.1038/s41392-024-01980-4.

A pathologically expanded, clonal lineage of IL-21-producing CD4+ T cells drives inflammatory neuropathy.

Seyedsadr M, Bang M, McCarthy E, Zhang S, Chen H, Mohebbi M J Clin Invest. 2024; 134(15).

PMID: 39087473 PMC: 11290969. DOI: 10.1172/JCI178602.

Transcriptional regulation of Tfh dynamics and the formation of immunological synapses.

Kim Y, Choi J, Choi Y Exp Mol Med. 2024; 56(6):1365-1372.

PMID: 38825646 PMC: 11263543. DOI: 10.1038/s12276-024-01254-7.

IL-17 and IL-21: Their Immunobiology and Therapeutic Potentials.

Koh C, Kim B, Kang C, Chung Y, Seo H Immune Netw. 2024; 24(1):e2.

PMID: 38455465 PMC: 10917578. DOI: 10.4110/in.2024.24.e2.

Cytokines in Follicular Helper T Cell Biology in Physiologic and Pathologic Conditions.

Choi J, Crotty S, Choi Y Immune Netw. 2024; 24(1):e8.

PMID: 38455461 PMC: 10917579. DOI: 10.4110/in.2024.24.e8.

References

Huber M, Brustle A, Reinhard K, Guralnik A, Walter G, Mahiny A . IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc Natl Acad Sci U S A. 2008; 105(52):20846-51. PMC: 2634912. DOI: 10.1073/pnas.0809077106. View

Turner Jr C, Mack D, Davis M . Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell. 1994; 77(2):297-306. DOI: 10.1016/0092-8674(94)90321-2. View

Ozaki K, Spolski R, Feng C, Qi C, Cheng J, Sher A . A critical role for IL-21 in regulating immunoglobulin production. Science. 2002; 298(5598):1630-4. DOI: 10.1126/science.1077002. View

Ozaki K, Kikly K, Michalovich D, Young P, Leonard W . Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc Natl Acad Sci U S A. 2000; 97(21):11439-44. PMC: 17218. DOI: 10.1073/pnas.200360997. View

Shaffer A, Yu X, He Y, Boldrick J, Chan E, Staudt L . BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity. 2000; 13(2):199-212. DOI: 10.1016/s1074-7613(00)00020-0. View

Martins G, Calame K . Regulation and functions of Blimp-1 in T and B lymphocytes. Annu Rev Immunol. 2008; 26:133-69. DOI: 10.1146/annurev.immunol.26.021607.090241. View

Schones D, Cui K, Cuddapah S, Roh T, Barski A, Wang Z . Dynamic regulation of nucleosome positioning in the human genome. Cell. 2008; 132(5):887-98. PMC: 10894452. DOI: 10.1016/j.cell.2008.02.022. View

Tamura T, Yanai H, Savitsky D, Taniguchi T . The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol. 2008; 26:535-84. DOI: 10.1146/annurev.immunol.26.021607.090400. View

Sciammas R, Shaffer A, Schatz J, Zhao H, Staudt L, Singh H . Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity. 2006; 25(2):225-36. DOI: 10.1016/j.immuni.2006.07.009. View

10.

Martins G, Cimmino L, Shapiro-Shelef M, Szabolcs M, Herron A, Magnusdottir E . Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat Immunol. 2006; 7(5):457-65. DOI: 10.1038/ni1320. View

11.

Diehl S, Schmidlin H, Nagasawa M, van Haren S, Kwakkenbos M, Yasuda E . STAT3-mediated up-regulation of BLIMP1 Is coordinated with BCL6 down-regulation to control human plasma cell differentiation. J Immunol. 2008; 180(7):4805-15. PMC: 2396731. DOI: 10.4049/jimmunol.180.7.4805. View

12.

Nurieva R, Chung Y, Hwang D, Yang X, Kang H, Ma L . Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008; 29(1):138-49. PMC: 2556461. DOI: 10.1016/j.immuni.2008.05.009. View

13.

Noguchi M, Yi H, Rosenblatt H, Filipovich A, Adelstein S, Modi W . Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993; 73(1):147-57. DOI: 10.1016/0092-8674(93)90167-o. View

14.

Zeng R, Spolski R, Casas E, Zhu W, Levy D, Leonard W . The molecular basis of IL-21-mediated proliferation. Blood. 2007; 109(10):4135-42. PMC: 1885510. DOI: 10.1182/blood-2006-10-054973. View

15.

Shaffer A, Emre N, Lamy L, Ngo V, Wright G, Xiao W . IRF4 addiction in multiple myeloma. Nature. 2008; 454(7201):226-31. PMC: 2542904. DOI: 10.1038/nature07064. View

16.

Gabriele L, Ozato K . The role of the interferon regulatory factor (IRF) family in dendritic cell development and function. Cytokine Growth Factor Rev. 2007; 18(5-6):503-10. DOI: 10.1016/j.cytogfr.2007.06.008. View

17.

Kallies A, Hawkins E, Belz G, Metcalf D, Hommel M, Corcoran L . Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat Immunol. 2006; 7(5):466-74. DOI: 10.1038/ni1321. View

18.

Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P . The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol. 2007; 8(9):958-66. DOI: 10.1038/ni1500. View

19.

Levy D, Darnell Jr J . Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002; 3(9):651-62. DOI: 10.1038/nrm909. View

20.

Dillon S, Nelson A, Hammond A, Sprecher C, Gross J, Johnston J . Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000; 408(6808):57-63. DOI: 10.1038/35040504. View