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IRF8 regulates myeloid and B lymphoid lineage diversification

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Abstract

Interferon regulatory factor 8 (IRF8) is a member of the IRF family of transcription factors whose members play critical roles in interferon (IFN) signaling pathways governing the establishment of innate immune responses by myeloid and dendritic cells. IRF8 is also expressed in lymphoid cells and recent studies have documented its involvement in B cell lineage specification, immunoglobulin light chain gene rearrangement, the distribution of mature B cells into the marginal zone and follicular B cell compartment, and the transcriptional regulation of critical elements of the germinal center reaction. Here we review the contributions of IRF8 to B cell development from hematopoietic stem cells in the bone marrow and its place in the hierarchical regulatory network governing specification and commitment to the B cell fate.

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References

  1. Busslinger M. Transcriptional control of early B cell development. Annu Rev Immunol. 2004;22:55–79.

    Article  PubMed  CAS  Google Scholar 

  2. Hardy RR, Kincade PW, Dorshkind K. The protean nature of cells in the B lymphocyte lineage. Immunity. 2007;26:703–14.

    Article  PubMed  CAS  Google Scholar 

  3. Medina KL, Pongubala JM, Reddy KL, Lancki DW, Dekoter R, Kieslinger M, et al. Assembling a gene regulatory network for specification of the B cell fate. Dev Cell. 2004;7:607–17.

    Article  PubMed  CAS  Google Scholar 

  4. Dakic A, Metcalf D, Di Rago L, Mifsud S, Wu L, Nutt SL. PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis. J Exp Med. 2005;201:1487–502.

    Article  PubMed  CAS  Google Scholar 

  5. Iwasaki H, Somoza C, Shigematsu H, Duprez EA, Iwasaki-Arai J, Mizuno S, et al. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood. 2005;106:1590–600.

    Article  PubMed  CAS  Google Scholar 

  6. Scott EW, Simon MC, Anastasi J, Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science. 1994;265:1573–7.

    Article  PubMed  CAS  Google Scholar 

  7. Lu R, Medina KL, Lancki DW, Singh H. IRF-4, 8 orchestrate the pre-B-to-B transition in lymphocyte development. Genes Dev. 2003;17:1703–8.

    Article  PubMed  CAS  Google Scholar 

  8. Driggers PH, Ennist DL, Gleason SL, Mak WH, Marks MS, Levi BZ, et al. An interferon gamma-regulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes. Proc Natl Acad Sci USA. 1990;87:3743–7.

    Article  PubMed  CAS  Google Scholar 

  9. Brass AL, Kehrli E, Eisenbeis CF, Storb U, Singh H. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev. 1996;10:2335–47.

    Article  PubMed  CAS  Google Scholar 

  10. Kuwata T, Gongora C, Kanno Y, Sakaguchi K, Tamura T, Kanno T, et al. Gamma interferon triggers interaction between ICSBP (IRF-8) and TEL, recruiting the histone deacetylase HDAC3 to the interferon-responsive element. Mol Cell Biol. 2002;22:7439–48.

    Article  PubMed  CAS  Google Scholar 

  11. Sharf R, Azriel A, Lejbkowicz F, Winograd SS, Ehrlich R, Levi BZ. Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. J Biol Chem. 1995;270:13063–9.

    Article  PubMed  CAS  Google Scholar 

  12. Bovolenta C, Driggers PH, Marks MS, Medin JA, Politis AD, Vogel SN, et al. Molecular interactions between interferon consensus sequence binding protein and members of the interferon regulatory factor family. Proc Natl Acad Sci USA. 1994;91:5046–50.

    Article  PubMed  CAS  Google Scholar 

  13. Rosenbauer F, Waring JF, Foerster J, Wietstruk M, Philipp D, Horak I. Interferon consensus sequence binding protein and interferon regulatory factor-4/Pip form a complex that represses the expression of the interferon-stimulated gene-15 in macrophages. Blood. 1999;94:4274–81.

    PubMed  CAS  Google Scholar 

  14. Nagulapalli S, Atchison ML. Transcription factor Pip can enhance DNA binding by E47, leading to transcriptional synergy involving multiple protein domains. Mol Cell Biol. 1998;18:4639–50.

    PubMed  CAS  Google Scholar 

  15. Zhu C, Rao K, Xiong H, Gagnidze K, Li F, Horvath C, et al. Activation of the murine interleukin-12 p40 promoter by functional interactions between NFAT and ICSBP. J Biol Chem. 2003;278:39372–82.

    Article  PubMed  CAS  Google Scholar 

  16. Alter-Koltunoff M, Ehrlich S, Dror N, Azriel A, Eilers M, Hauser H, et al. Nramp1-mediated innate resistance to intraphagosomal pathogens is regulated by IRF-8, PU.1, and Miz-1. J Biol Chem. 2003;278:44025–32.

    Article  PubMed  CAS  Google Scholar 

  17. Tamura T, Thotakura P, Tanaka TS, Ko MS, Ozato K. Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages. Blood. 2005;106:1938–47.

    Article  PubMed  CAS  Google Scholar 

  18. Xiong H, Li H, Kong HJ, Chen Y, Zhao J, Xiong S, et al. Ubiquitin-dependent degradation of interferon regulatory factor-8 mediated by Cbl down-regulates interleukin-12 expression. J Biol Chem. 2005;280:23531–9.

    Article  PubMed  CAS  Google Scholar 

  19. Kong HJ, Anderson DE, Lee CH, Jang MK, Tamura T, Tailor P, et al. Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages. J Immunol. 2007;179:26–30.

    PubMed  CAS  Google Scholar 

  20. Holtschke T, Lohler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, et al. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell. 1996;87:307–17.

    Article  PubMed  CAS  Google Scholar 

  21. Giese NA, Gabriele L, Doherty TM, Klinman DM, Tadesse-Heath L, Contursi C, et al. Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression. J Exp Med. 1997;186:1535–46.

    Article  PubMed  CAS  Google Scholar 

  22. Turcotte K, Gauthier S, Tuite A, Mullick A, Malo D, Gros P. A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia-like syndrome in BXH-2 mice. J Exp Med. 2005;201:881–90.

    Article  PubMed  CAS  Google Scholar 

  23. Tamura T, Nagamura-Inoue T, Shmeltzer Z, Kuwata T, Ozato K. ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. Immunity. 2000;13:155–65.

    Article  PubMed  CAS  Google Scholar 

  24. Gabriele L, Ozato K. The role of the interferon regulatory factor (IRF) family in dendritic cell development and function. Cytokine Growth Factor Rev. 2007;18:503–10.

    Article  PubMed  CAS  Google Scholar 

  25. Ozato K, Shin D-M, Chang T-H, Morse HC, 3rd. TRIM family proteins and their emerging role in innate immunity. Nat Rev Immunol. 2008. in press.

  26. Lee CH, Melchers M, Wang H, Torrey TA, Slota R, Qi CF, et al. Regulation of the germinal center gene program by IFN regulatory factor 8/IFN consensus sequence binding protein. J Exp Med. 2006;203:63–72.

    Article  PubMed  CAS  Google Scholar 

  27. Martinez A, Pittaluga S, Rudelius M, Davies-Hill T, Sebasigari D, Fountaine TJ, et al. Expression of the interferon regulatory factor 8/ICSBP-1 in human reactive lymphoid tissues and B-cell lymphomas: a novel germinal center marker. Am J Surg Pathol. 2008;32:1190–200.

    Article  PubMed  Google Scholar 

  28. Hardy RR, Hayakawa K. B cell development pathways. Annu Rev Immunol. 2001;19:595–621.

    Article  PubMed  CAS  Google Scholar 

  29. Rolink A, Grawunder U, Winkler TH, Karasuyama H, Melchers F. IL-2 receptor α chain (CD25, TAC) expression defines a crucial stage in pre-B cell development. Int Immunol. 1994;6:1257–64.

    Article  PubMed  CAS  Google Scholar 

  30. Wang H, Lee CH, Qi CF, Tailor P, Feng J, Abbasi S, Atsumi T, Morse HC, 3rd. IRF8 regulates B cell lineage specification, commitment and differentiation. Blood 2008. in press.

  31. Scheller M, Foerster J, Heyworth CM, Waring JF, Lohler J, Gilmore GL, et al. Altered development and cytokine responses of myeloid progenitors in the absence of transcription factor, interferon consensus sequence binding protein. Blood. 1999;94:3764–71.

    PubMed  CAS  Google Scholar 

  32. DeKoter RP, Singh H. Regulation of B lymphocyte and macrophage development by graded expression of PU.1. Science. 2000;288:1439–41.

    Article  PubMed  CAS  Google Scholar 

  33. Singh H, DeKoter RP, Walsh JC. PU.1, a shared transcriptional regulator of lymphoid and myeloid cell fates. Cold Spring Harb Symp Quant Biol. 1999;64:13–20.

    Article  PubMed  CAS  Google Scholar 

  34. Li Y, Okuno Y, Zhang P, Radomska HS, Chen H, Iwasaki H, et al. Regulation of the PU.1 gene by distal elements. Blood. 2001;98:2958–65.

    Article  PubMed  CAS  Google Scholar 

  35. Okuno Y, Huang G, Rosenbauer F, Evans EK, Radomska HS, Iwasaki H, et al. Potential autoregulation of transcription factor PU.1 by an upstream regulatory element. Mol Cell Biol. 2005;25:2832–45.

    Article  PubMed  CAS  Google Scholar 

  36. Ebralidze AK, Guibal FC, Steidl U, Zhang P, Lee S, Bartholdy B, et al. PU.1 expression is modulated by the balance of functional sense and antisense RNAs regulated by a shared cis-regulatory element. Genes Dev. 2008;22:2085–92.

    Article  PubMed  CAS  Google Scholar 

  37. Pongubala JM, Northrup DL, Lancki DW, Medina KL, Treiber T, Bertolino E, et al. Transcription factor EBF restricts alternative lineage options and promotes B cell fate commitment independently of Pax5. Nat Immunol. 2008;9:203–15.

    Article  PubMed  CAS  Google Scholar 

  38. Zou GM, Chen JJ, Yoder MC, Wu W, Rowley JD. Knockdown of Pu.1 by small interfering RNA in CD34+ embryoid body cells derived from mouse ES cells turns cell fate determination to pro-B cells. Proc Natl Acad Sci USA. 2005;102:13236–41.

    Article  PubMed  CAS  Google Scholar 

  39. Stirewalt DL, Choi YE, Sharpless NE, Pogosova-Agadjanyan EL, Cronk MR, Yukawa M, Larson EB, Wood BL, Appelbaum FR, Radich JP, Heimfeld S. Decreased IRF8 expression found in aging hematopoietic progenitor/stem cells. Leukemia. 2008. in press.

  40. Liang Y, Van Zant G, Szilvassy SJ. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood. 2005;106:1479–87.

    Article  PubMed  CAS  Google Scholar 

  41. Ma S, Pathak S, Trinh L, Lu R. Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B-cell receptor and promote cell-cycle withdrawal in pre-B-cell development. Blood. 2008;111:1396–403.

    Article  PubMed  CAS  Google Scholar 

  42. Pridans C, Holmes ML, Polli M, Wettenhall JM, Dakic A, Corcoran LM, et al. Identification of Pax5 target genes in early B cell differentiation. J Immunol. 2008;180:1719–28.

    PubMed  CAS  Google Scholar 

  43. O’Riordan M, Grosschedl R. Coordinate regulation of B cell differentiation by the transcription factors EBF and E2A. Immunity. 1999;11:21–31.

    Article  PubMed  CAS  Google Scholar 

  44. Roessler S, Gyory I, Imhof S, Spivakov M, Williams RR, Busslinger M, et al. Distinct promoters mediate the regulation of Ebf1 gene expression by interleukin-7 and Pax5. Mol Cell Biol. 2007;27:579–94.

    Article  PubMed  CAS  Google Scholar 

  45. Dakic A, Wu L, Nutt SL. Is PU.1 a dosage-sensitive regulator of haemopoietic lineage commitment and leukaemogenesis? Trends Immunol. 2007;28:108–14.

    Article  PubMed  CAS  Google Scholar 

  46. Ma S, Turetsky A, Trinh L, Lu R. IFN regulatory factor 4 and 8 promote Ig light chain kappa locus activation in pre-B cell development. J Immunol. 2006;177:7898–904.

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Drs. Keiko Ozato and Prafullakumar Tailor, NICHD, for providing BXH2 mice, and members of LIP and the Ozato laboratory for many helpful discussions. This study was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases.

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Correspondence to Hongsheng Wang.

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Wang, H., Morse, H.C. IRF8 regulates myeloid and B lymphoid lineage diversification. Immunol Res 43, 109–117 (2009). https://doi.org/10.1007/s12026-008-8055-8

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