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Transcription factors TFE3 and TFEB are critical for CD40 ligand expression and thymus-dependent humoral immunity

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Abstract

TFE3 and TFEB are broadly expressed transcription factors related to the transcription factor Mitf. Although they have been linked to cytokine signaling pathways in nonlymphoid cells, their function in T cells is unknown. TFE3-deficient mice are phenotypically normal, whereas TFEB deficiency causes early embryonic death. We now show that combined inactivation of TFE3 and TFEB in T cells resulted in a hyper–immunoglobulin M syndrome due to impaired expression of CD40 ligand by CD4+ T cells. Native TFE3 and TFEB bound to multiple cognate sites in the promoter of the gene encoding CD40 ligand (Cd40lg), and maximum Cd40lg promoter activity and gene expression required TFE3 or TFEB. Thus, TFE3 and TFEB are direct, physiological and mutually redundant activators of Cd40lg expression in activated CD4+ T cells critical for T cell–dependent antibody responses.

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Figure 1: TFE3 and TFEB expression in T cells and TDN protein expression in TDN-transgenic mice.
Figure 2: Distribution of the predominant B cell and T cell populations in TDN-transgenic mice.
Figure 3: Impaired germinal center formation in TDN-transgenic mice.
Figure 4: Impaired T cell–dependent but intact T cell–independent humoral responses in TDN-transgenic mice.
Figure 5: Inactivation of TFE3 and TFEB in CD4 T cells impairs induction of CD40L expression but not the synthesis of other activation and effector molecules.
Figure 6: T cell–dependent IgG responses in TDN-transgenic mice can be restored by CD40 stimulation in vivo.
Figure 7: TFE3 and TFEB bind to the Cd40lg promoter in vivo and in vitro.
Figure 8: Maximum Cd40lg promoter activity requires binding of native TFE3 and TFEB.

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Change history

  • 07 September 2006

    In the version of this article initially published online, the title of the first subheading in the results section was incorrect. The correct title is "MiT inactivation in T cells causes hyper-IgM syndrome". The error has been corrected for all versions of the article.

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Acknowledgements

We thank L. Braithwaite-Harte and S. Mirra (Department of Pathology, State University of New York, Downstate Medical Center at Brooklyn) for sharing expertise and reagents for histology; H. Siddiqi (Department of Microbiology and Immunology, State University of New York, Downstate Medical Center at Brooklyn) for help in establishing ELISAs; O. Ramadan for technical assistance in mouse genotyping; K. Calame (Columbia University, New York, New York) for sharing unpublished results and discussions; K. Alexandropoulos (Columbia University, New York, New York), W. Pear (University of Pennsylvania, Philadelphia, Pennsylvania) and A. Pernis (Columbia University New York, New York) for critical reading of the manuscript, advice and discussions; and P. Cortes and lab members (Mount Sinai School of Medicine, New York, New York) for providing access to their laboratory for primary T cell transfection studies. Supported by the Dean's Initiative Pilot Project (State University of New York, Downstate Medical Center; C.A.J.R.) and the National Institutes of Health (DK65011 to C.A.J.R.).

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Authors and Affiliations

  1. Program in Molecular and Cellular Biology, The School of Graduate Studies, State University of New York, Downstate Medical Center at Brooklyn, New York, 11203, New York, USA

    Chongmin Huan & Christopher A J Roman

  2. Department of Microbiology and Immunology and the Morse Institute for Molecular Genetics, State University of New York, Downstate Medical Center at Brooklyn, New York, 11203, New York, USA

    Chongmin Huan, Matthew L Kelly, Ryan Steele & Christopher A J Roman

  3. Department of Medicine, Division of Hematology and Oncology, State University of New York, Downstate Medical Center at Brooklyn, New York, 11203, New York, USA

    Iuliana Shapira

  4. Department of Pathology, State University of New York, Downstate Medical Center at Brooklyn, New York, 11203, New York, USA

    Susan R S Gottesman

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  1. Chongmin Huan
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  2. Matthew L Kelly
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Contributions

C.H. and C.A.J.R. conceptualized and designed the research; C.H. created the TDN-transgenic mice and did most of the experimental work with the technical assistance of M.L.K.; R.S. did ELISAs with the assistance of C.H.; I.S. and S.R.S.G. prepared and analyzed spleen sections in conjunction with C.H.; C.A.J.R. and C.H. conceptualized and wrote the manuscript with input from S.R.S.G.; C.A.J.R. supervised the project.

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Correspondence to Christopher A J Roman.

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Competing interests

C.H. and C.A.J.R. are named on provisional patent R1545-100, “Method for Treating Immune Dysfunction by Regulation of CD40L Expression,” filed in December 2005 by the Research Foundation of the State University of New York.

Supplementary information

Supplementary Fig. 1

TFE3, TFEB and Mitf expression. (PDF 452 kb)

Supplementary Fig. 2

TDN-Tg description and inhibition of TFEB expression by slRNAi. (PDF 218 kb)

Supplementary Fig. 3

Characterization of interactions of TFE3 and TFEB with each other and DNA. (PDF 572 kb)

Supplementary Fig. 4

Native TFE3 and TFEB are important for CD40L expression in Jurkat T cells. (PDF 170 kb)

Supplementary Table 1

Oligonucleotides for EMSA. (PDF 97 kb)

Supplementary Table 2

Oligonucleotides for cloning Cd40lg and CD40LG promoters and for E-box mutagenesis. (PDF 99 kb)

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Huan, C., Kelly, M., Steele, R. et al. Transcription factors TFE3 and TFEB are critical for CD40 ligand expression and thymus-dependent humoral immunity. Nat Immunol 7, 1082–1091 (2006). https://doi.org/10.1038/ni1378

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