Transcription factors TFE3 and TFEB are critical for CD40 ligand expression and thymus-dependent humoral immunity.
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.
Huan
Chongmin
C
Program in Molecular and Cellular Biology, The School of Graduate Studies, State University of New York, Downstate Medical Center at Brooklyn, New York, New York 11203, USA.
Kelly
Matthew L
ML
Steele
Ryan
R
Shapira
Iuliana
I
Gottesman
Susan R S
SR
Roman
Christopher A J
CA
D000818:Animals; D000917:Antibody Formation / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000819:agonists / Q000032:analysis / Q000235:genetics*; D005786:Gene Expression Regulation; D053306:Hyper-IgM Immunodeficiency Syndrome / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D013950:Thymus Gland / Q000276:immunology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C484068:Tcfeb protein, mouse; C068486:Tcfe3 protein, mouse; D023201:CD40 Ligand